rules&guidance for pharmaceutical manufacturers orang press2007

Rules and Guidancefor PharmaceuticalManufacturers and

Distributors 2007

Guidance dna seluRlacituecamrahP rof

dna srerutcafunaMsrotubirtsiD 7002

Compiled by the Inspection and Standards Division of the Medicines and Healthcare products Regulatory Agency

London • Chicago

Published by the Pharmaceutical PressAn imprint of RPS Publishing

1 Lambeth High Street, London SE1 7JN, UK100 South Atkinson Road, Suite 200, Grayslake, IL 60030-7820, USA

c© Crown Copyright 2007

Medicines and Healthcare products Regulatory AgencyMarket Towers 1 Nine Elms LaneLondon SW8 5NQInformation on re-use of crown copyright information can be found on the MHRAwebsite: www.mhra.gov.uk

Designed and published by the Pharmaceutical Press 2007

is a trade mark of RPS Publishing

RPS Publishing is the publishing organisation of the Royal Pharmaceutical Society ofGreat Britain

First edition published in 1971 as the Guide to Good Pharmaceutical ManufacturingPractice, second edition in 1977, third edition 1983, fourth edition as the Rules andGuidance for Pharmaceutical Manufacturers in 1993, fifth edition as the Rules andGuidance for Pharmaceutical Manufacturers and Distributors in 1997, sixth edition in2002.

Previously published by The Stationery Office (TSO), 2002.

Typeset by Techbooks, New Delhi, IndiaPrinted in Great Britain by Cambridge University Press, Cambridge

ISBN 978 0 85369 719 0

All rights reserved. No part of this publication may be reproduced, stored in a retrievalsystem, or transmitted in any form or by any means, without the prior written permis-sion of the copyright holder.

The publisher makes no representation, express or implied, with regard to the accu-racy of the information contained in this book and cannot accept any legal responsibilityor liability for any errors or omissions that may be made.

Website listings published in this guide other than www.mhra.gov.uk are not underMHRA control, therefore we are not responsible for the availability or content of anysite. Listings should not be taken as an endorsement of any kind and we accept noliability in respect of these sites.

A catalogue record for this book is available from the British Library.

Reprinted 2007

Contents

Preface to the 2007 edition xi

Acknowledgements xv

Feedback xvi

Introduction xvii

Section I: Medicines and Healthcare products RegulatoryAgency (MHRA) 1

1 MHRA: Licensing, Inspection and Enforcement for HumanMedicines 3

Overview of MHRA 3Inspectorate 4Licensing Office 6Defective Medicines Report Centre (DMRC) 6Enforcement and Intelligence Group 7Advice 7

Section II: Guidance on Good Manufacturing Practice (GMP) 9

The MHRA Index to the EU Guide to GMP 11

2 EU Guidance on Good Manufacturing Practice 38

PART IBasic Requirements for Medicinal Products 38

Introduction 401 Quality Management 43

Principle 43Quality Assurance 43

v

vi CONTENTS

Good Manufacturing Practice for Medicinal Products (GMP) 44Quality Control 45Product Quality Review 46

2 Personnel 48Principle 48General 48Key Personnel 48Training 50Personnel Hygiene 51

3 Premises and Equipment 53Principle 53Premises 53Equipment 56

4 Documentation 58Principle 58General 58Documents Required 59Manufacturing Formula and Processing Instructions 60Packaging Instructions 61Batch Processing Records 62Batch Packaging Records 62Procedures and Records 63

5 Production 66Principle 66General 66Prevention of Cross-contamination in Production 67Validation 68Starting Materials 68Processing Operations: intermediate and bulk products 70Packaging Materials 70Packaging Operations 70Finished Products 72Rejected, Recovered and Returned Materials 72

6 Quality Control 74Principle 74General 74Good Quality Control Laboratory Practice 75

7 Contract Manufacture and Analysis 80Principle 80General 80The Contract Giver 80The Contract Acceptor 81The Contract 81

CONTENTS vii

8 Complaints and Product Recall 83Principle 83Complaints 83Recalls 84

9 Self Inspection 85Principle 85

Annexes 86Annex 1 Manufacture of Sterile Medicinal Products 86Annex 2 Manufacture of Biological Medicinal Products for

Human Use 103Annex 3 Manufacture of Radiopharmaceuticals 110Annex 4 Manufacture of Veterinary Medicinal Products Other

Than Immunological Veterinary MedicinalProducts 112

Annex 5 Manufacture of Immunological VeterinaryMedicinal Products 115

Annex 6 Manufacture of Medicinal Gases 127Annex 7 Manufacture of Herbal Medicinal Products 137Annex 8 Sampling of Starting and Packaging Materials 140Annex 9 Manufacture of Liquids, Creams and Ointments 142Annex 10 Manufacture of Pressurised Metered Dose Aerosol

Preparations for Inhalation 144Annex 11 Computerised Systems 146Annex 12 Use of Ionising Radiation in the Manufacture of

Medicinal Products 149Annex 13 Manufacture of Investigational Medicinal

Products 156Annex 14 Manufacture of Medicinal Products Derived From

Human Blood or Plasma 172Annex 15 Qualification and Validation 179Annex 16 Certification by a Qualified Person and Batch

Release 187Annex 17 Parametric Release 197Annex 18 Good Manufacturing Practice for Active

Pharmaceutical Ingredients 200Annex 19 Reference and Retention Samples 201Glossary of Terms Used in the EU Guide to GMP 207

PART IIBasic Requirements for Active Substances Used as Starting Materials 214

1 Introduction 2162 Quality Management 2193 Personnel 222

viii CONTENTS

4 Buildings and Facilities 2235 Process Equipment 2266 Documentation and Records 2297 Materials Management 2348 Production and In-Process Controls 2379 Packaging and Identification Labelling of APIs and

Intermediates 24010 Storage and Distribution 24211 Laboratory Controls 24312 Validation 24713 Change Control 25214 Rejection and Re-Use of Materials 25215 Complaints and Recalls 25416 Contract Manufacturers (including Laboratories) 25517 Agents, Brokers, Traders, Distributors, Repackers, and

Relabellers 25618 Specific Guidance for APIs Manufactured by Cell

Culture/Fermentation 25819 APIs for Use in Clinical Trials 26220 Glossary 264

3 UK Guidance on Manufacture 271

Manufacturers’ Obligations 272Qualified Persons 275Code of Practice for Qualified Persons in the Pharmaceutical

Industry 276Appendix 1: UK Statements on CPD 287Import from Third Countries 290Mutual Recognition Agreements on Good Manufacturing Practice

(GMP) and Manufacturing Authorisation 290Content of the Fabricator’s/Manufacturer’s Batch Certificate for

Drug/Medicinal Products Exported to Countries Under the Scopeof a Mutual Recognition Agreement (MRA) 291

UK Guidance on Certificates of Analysis 292GMP for Starting Materials 293Manufacture and Importation of Unlicensed Medicines for

Human Use 294

Section III: Legislation on Manufacture 297

4 EU Legislation on Manufacture 299

Directive 2001/83/EC, as Amended, Title IV, Manufactureand Importation 300

CONTENTS ix

Directive 2003/94/EC, Laying Down the Principles andGuidelines of Good Manufacturing Practice for HumanMedicines 306

5 UK Legislation on Manufacture 315

The Medicines for Human Use (Manufacturing, WholesaleDealing and Miscellaneous Amendments) Regulations 2005(SI 2005 No. 2789) 316

Schedule 1 of the Regulations 323Schedule 2 of the Regulations 326Schedule 3 of the Regulations 329Prescribed Conditions for Manufacturer’s Undertakings for

Imported Products (SI 1977 No. 1038) 335Schedule 335

Section IV: Guidance on Wholesale Distribution Practice 339

6 EU Guidance on Wholesale Distribution Practice 341

Guidelines on Good Distribution Practice of MedicinalProducts for Human Use (94/C 63/03) 341

7 UK Guidance on Wholesale Distribution Practice 349

Wholesale Dealer’s Obligations 349Appointment and Duties of the Responsible Person 355Control and Monitoring of Storage and Transportation Temperatures 357Counterfeits/Ensuring Bona Fides 359Diverted Medicines 360Parallel Distribution 361Continued Supply 363Product Recall/Withdrawal 366

Section V: Legislation on Wholesale Distribution 369

8 EU Legislation on Wholesale Distribution 371

Directive 2001/83/EC, as Amended, Title VII, Wholesaledistribution 371

9 UK Legislation on Wholesale Distribution 377

The Medicines for Human Use (Manufacturing, Wholesale Dealingand Miscellaneous Amendments) Regulations 2005(SI 2005 No. 2789) 377

x CONTENTS

Section VI: Glossary of Legislation 387

Glossary of Legislation 389

European Legislation 389Primary (UK) Legislation 389Secondary Legislation (UK Statutory Instruments) 390

Section VII: Index 393

Preface to the 2007 edition

Since the 2002 edition of Rules and Guidance for Pharmaceutical Manu-facturers and Distributors (the “Orange Guide”) there have been manychanges and additions to the detailed European Community guidelines onGood Manufacturing Practice (GMP). In addition, there is a new Directivedealing specifically with GMP and the Community code relating to medici-nal products for human use (Council Directive 2001/83/EC) has itself beenthe subject of substantial revision, via amending Directive 2004/27/EC,and these changes have been transposed into UK domestic legislation.

GMP Directive

The principles and guidelines of GMP are adopted by the European Com-mission under powers conferred by Council Directive 2001/83/EC. Theobjective of GMP is to ensure that products are consistently produced andcontrolled to particular quality standards.

Commission Directive 2003/94/EC (the “GMP Directive”) sets outnew requirements relating to the implementation of good manufacturingpractice for medicinal products for human use (including InvestigationalMedicinal Products). The GMP Directive broadens the definition of goodmanufacturing practice set out in Directive 91/356/EEC and repealed theprevious Directive in its entirety.

Changes to the Community Code

The amendments made by Directive 2004/27/EC in relation to manu-facturing, wholesale dealing, supervision and sanctions are contained inArticles 1(32) to (39) and (55) to (60), (77) and (78). These provisionswere implemented in the United Kingdom (along with some other miscella-neous “tidying-up” changes) by making regulations amending the relevantprovisions of the Medicines Act 1968. The new arrangements came intoforce on 30 October 2005. The headline changes are as follows:

xi

xii PREFACE TO THE 2007 EDITION

� New Community requirements1 on pharmaceutical companies to adhereto the principles of GMP in the manufacturing processes of active sub-stances used as starting materials. This includes any repackaging or re-labelling activities carried out by a distributor or broker.

� New duty on QPs extending the need for full batch analysis and test-ing2 (or re-testing) in a Member State to product imported from thirdcountries (i.e. outside the Community), whether or not the product wasoriginally manufactured in the Community.

� A new requirement3 for distributors that import medicinal productsfrom other Member States to notify the marketing authorisation holderand the competent authority of the Member State to which the productis imported of the intention to import.

� New powers4 for the competent authority to carry out unannouncedinspections at the premises of manufacturers of starting materials, or atthe premises of marketing authorisation holders or any firms employedby the marketing authorisation holder where there are grounds for sus-pecting non-compliance with GMP principles.

� Changes to the system of licensing for third country imports. The impor-tation of products from third countries now requires a manufacturingauthorisation for import, rather than, as previously, a wholesale dealer’simport licence.

UK legislation

New regulations5 were introduced on 30 October 2005 to replace theStandard Provisions Regulations,6 in relation to relevant medicinal prod-ucts, i.e. medicinal products to which Directive 2001/83/EC as amended,apply. The previous Standard Provision Regulations, themselves, had

1 Articles 1(33)–(35) of Directive 2004/27/EC amending Articles 46, 46a and 47of Directive 2001/83/EC.

2 Articles 1(36)–(38) of Directive 2004/27/EC amending Articles 49–50 of Direc-tive 2001/83/EC.

3 Article 1(55) of Directive 2004/27/EC amending Article 76 of Directive2001/83/EC.

4 Article 1(77) of Directive 2004/27/EC amending Article 111 of Directive2001/83/EC.

5 The Medicines for Human Use (Manufacturing, Wholesale Dealing and Miscel-laneous Amendments) Regulations 2005 (SI 2005 No. 2789).

6 The Medicines (Standard Provisions for Licences and Certificates) Regulations1971 (SI 1971/972)

PREFACE TO THE 2007 EDITION xiii

been amended nine times over the years. The Medicines for Human use(Manufacturing, Wholesale Dealing and Miscellaneous Amendments) Reg-ulations 2005 match the amended European Directive requirements onmedicines for human use.

Changes to the EU Guide to GMP

Following a restructuring of the GMP Guide publication, guidance on BasicRequirements for Active Substances used as Starting Materials (formerlyAnnex 18) now becomes the new Part II to the EC GMP Guide.

New/revised chapters

Chapter 1 has been revised to include new text on Product Quality Review,October 2005. A revised version, containing details of significant qual-ity system-related responsibilities for monitoring, reporting, reviewing andtrending requirements came into operation 1 January 2006.

Chapter 6 the revised version (October 2005) includes the on-goingstability programme, which came into operation on 1 June 2006.

Chapter 8 was revised in December 2005 to include new requirements oncounterfeit products, plus other minor modifications. The revised versioncame into operation on 1 February 2006.

New/revised annexes

Annex 1 (Manufacture of Sterile Medicinal Products): minor revisionsmade in September 2003.

Annex 13 (Manufacture of Investigational Medicinal Products):updated, with major revisions, July 2003.

Annex 19 (Reference and Retention Samples): a new annex, with detailedrequirements, came into operation in June 2006.

Changes on the horizon

Two new sections are planned to the EC Guide to GMP. These relate to ICHQ9 and Q10, i.e. Quality Risk Management and Quality Systems. Thesemay form new annexes to the Guide (Annexes 20 and 21, respectively) orthey may form a separate part (Part III). Adoption is expected during 2007or 2008.

In addition, further changes are expected during 2007 or 2008 relatingto Chapter 4 and in respect of the following annexes: 2, 3, 6, 7, 11, 13and 16.

xiv PREFACE TO THE 2007 EDITION

The “Orange Guide’’ 2007

Many of the European Directives on medicinal products issued over thelast thirty-five years were consolidated into two Directives during 2001,one for products used in humans and one for veterinary products. Thismakes the requirements more accessible. Although it is UK legislation,implementing the Directives, that bears directly on activities in the UK, itis often helpful for manufacturers and wholesalers to be aware of the orig-inal EU obligations. This is particularly so when trading across boundariesof Member States. Therefore, as before, the “Titles” or sections of Direc-tive 2001/83/EC, as amended, dealing with manufacture and wholesaledistribution of products for human use are included in this edition.

The UK’s Code of Practice for Qualified Persons has been updated bythe professional bodies in consultation with the MHRA; this is included.

Recommendations on meeting the important requirement to ensure the“proper conservation and distribution” of medicines requiring storagebelow ambient temperature (“cold-chain distribution”) have been devel-oped between representatives of wholesalers and the MHRA. These werepublished originally in the Pharmaceutical Journal,7 were summarised inMAIL,8 and are reproduced here in updated form.

Finally, there is a new section on the activities and services of the Inspec-tion and Standards Division of the MHRA, which will be of interest tomanufacturers and wholesalers.

Although much of the text in this book is available in its original form inother places, including various websites, we are pleased that the “OrangeGuide” continues to satisfy a demand for information in one authorita-tive and convenient place. In particular, the detailed index to the OrangeGuide adds value and simplifies the navigation of these complex docu-ments. Readers are invited to suggest further updates to the Index, to theMHRA, for future improvements in navigation and cross-referencing.

For the 2007 version, we have, for the first time made the entire OrangeGuide available online, as part of “MedicinesComplete” – a subscription-based database of leading medicines and healthcare references – and viaCD-ROM. Also available is a separate GDP booklet for the wholesaledealing market. We hope that this new edition and the new formats willcontinue to be useful.

Gerald HeddellDirector, Inspection and Standards Division

December 2006

7 Taylor J. Recommendations on the control and monitoring of storage and trans-portation temperatures of medicinal products. Pharm J 2001; 267: 128–131.

8 MCA Newsletter MAIL, Issue 131, May/June 2002.

Acknowledgements

To the European Commission for permission to reproduce the text of theDirectives, the EC Guide to GMP and the guidelines on Good DistributionPractice.

To the Institute of Biology, the Royal Pharmaceutical Society of GreatBritain and the Royal Society of Chemistry for permission to reproducethe texts of the Code of Practice for Qualified Persons.

xv

Feedback

Comments on the content or presentation of the Orange Guide are encour-aged and will be used to develop further editions. Your views are valuedand both MHRA and Pharmaceutical Press would appreciate you takingthe time to contact us. Please use the reply card enclosed with this editionor contact us directly by post, telephone, fax or email.

“The Orange Guide”The MHRA Information CentreRoom 10-2Medicines and Healthcare products Regulatory AgencyMarket Towers1 Nine Elms LaneLondon SW8 5NQUKTel: +44 (0)20 7084Fax: +44 (0)20 7084 2353E-mail: [email protected]

xvi

2000

Introduction

This publication brings together the main pharmaceutical regulations,directives and guidance which manufacturers and wholesalers are expectedto follow when making and distributing medicinal products in the Euro-pean Union and European Economic Area.1 It is of particular relevance toall holders of manufacturer’s licences and wholesale dealer’s licences andto their Qualified Persons (QPs) and Responsible Persons (RPs), who havea responsibility for ensuring compliance with many of these regulatoryrequirements.

The obligation on governments of all Member States of the EuropeanUnion to ensure that pharmaceutical manufacturers are authorised is statedin Title IV of Directive 2001/83/EC, as amended (products for human use)and of Directive 2001/82/EC (veterinary products). These titles, or sections,are also the source of requirements for compliance with Good Manufactur-ing Practice (GMP), employment of QPs and repeated inspections by theregulatory authorities. Title VII of the same Directive requires all wholesaledistributors to be authorised, to have available RPs and comply with theguidelines on Good Distribution Practice (GDP).

The principles and guidelines of GMP are set out in two CommissionDirectives: 2003/94/EC for medicinal products for human use (replacingDirective 91/356/EEC) and 91/412/EEC for veterinary medicinal products.In the United Kingdom, the provisions for manufacturers and wholesaledealers have been implemented by requirements and undertakings incor-porated in regulations2 made under the Medicines Act 1968. Compliancewith the principles and guidelines of GMP is a statutory requirement.The European Community (EC) Guide to GMP3 (including its annexes)

1 The member states of the European Community plus Iceland, Liechtenstein andNorway.

2 The Medicines for Human Use (Manufacturing, Wholesale dealing and Miscel-laneous Amendments) Regulations 2005 [S.I. 2005/2789].

3 Commission of the European Communities. The rules governing medicinal prod-ucts in the European Community. Vol IV. Good Manufacturing Practice formedicinal products.

xvii

xviii INTRODUCTION

provides detailed guidance which interprets and expands on the statutoryprinciples and guidelines. Changes in technical knowledge and in regula-tions are reflected by additional and revised annexes.

GMP includes elements of the International Standard for Quality Man-agement Systems ISO 9001:2000 with additional requirements specific tomedicines. The UK first produced a national guide to GMP (known tradi-tionally as the Orange Guide) in 1971. Guidance on good pharmaceuticalwholesaling practice was added in the 1977 edition and a further editionwas produced in 1983. The EC guidance, first issued for GMP in 1989and for GDP in 1993, supersedes this and all other national guides ofMember States, although much that was familiar in the old UK Guide canstill be recognised in the EC guidance. The Pharmaceutical Inspection Co-operation Scheme has adopted the text of the EC Guide to GMP ensuringharmonisation of guidelines by its member inspectorates throughout theworld. Mutual Recognition Agreements between the EC and several thirdcountries have recognised the equivalence of GMP requirements of theparties concerned.

Manufacturers are required to name a QP on their manufacturer’slicence. No batch of medicinal product may be released to the marketwithin the EU unless a nominated QP has certified that it has been manu-factured and checked in compliance with the laws in force. Guidance toQPs in fulfilling their responsibilities is given in the EC Guide to GMP andin the Code of Practice4 for Qualified Persons which they are expected tofollow. In similar spirit, wholesalers are required to appoint a RP who hasthe knowledge and responsibility to ensure that correct procedures are fol-lowed during distribution. Notes on the qualifications and duties of RPsare given to assist this.

The aim of GMP and GDP is to assure the quality of the medicinal prod-uct for the safety, well-being and protection of the patient. In achieving thisaim it is impossible to over-emphasise the importance of people, at all levels,in the assurance of the quality of medicinal products. This is emphasised inthe first principle in the EC Guide to GMP. The great majority of reporteddefective medicinal products has resulted from human error or careless-ness, not from failures in technology. All the people involved with the pro-duction, Quality Control or distribution of medicinal products, whetherkey personnel, production or control or warehouse staff, inspectors of aregulatory authority or others involved in the many activities which leadto a patient taking a medicine, should bear this constantly in mind whenperforming their duties.

4 The Institute of Biology, The Royal Pharmaceutical Society of Great Britain, TheRoyal Society of Chemistry. Code of Practice for Qualified Persons. In: Registerof Qualified Persons. London: Institute of Biology, Royal Pharmaceutical Societyof Great Britain, Royal Society of Chemistry, 2004.

SECTION

I

MEDICINES ANDHEALTHCAREPRODUCTSREGULATORYAGENCY (MHRA)

CHAPTER

1

MHRA: Licensing, Inspection andEnforcement for Human Medicines

Contents

Overview of MHRA 3Inspection and Standards Division 4Inspectorate 4Good Manufacturing Practice

(GMP) 4Good Distribution Practice

(GDP) 5Good Laboratory Practice

(GLP) 5Good Clinical Practice (GCP) 5

Good Pharmacovigilance Practice(GPvP) 5

Licensing Office 6Defective Medicines Report Centre

(DMRC) 6Enforcement and Intelligence

Group 7Advice 7

Overview of MHRA

In Ministers announced that the Medicines Control Agency and theMedical Devices Agency would be merged to form a new agency. The newagency is known as the Medicines and Healthcare products RegulatoryAgency (MHRA). Its key objective is to protect the health of the public byensuring that medicines, healthcare products and medical equipment aresafe.

All licensed medicines available in the UK are subject to rigorous scrutinyby the MHRA before they can be used by patients. This ensures thatmedicines meet acceptable standards on safety, quality and efficacy. It isthe responsibility of the MHRA and the expert advisory bodies set up bythe Medicines Act to ensure that the sometimes difficult balance betweensafety and effectiveness is achieved. MHRA experts assess all applicationsfor new medicines to ensure they meet the required standards. This is fol-lowed up by a system of inspection and testing which continues throughoutthe lifetime of the medicine.

The roles of the MHRA are to:

� provide a system of post-marketing surveillance for reporting, investigat-ing and monitoring of adverse drug reactions to medicines and medicaldevices;

3

2002,

4 I MEDICINES AND HEALTHCARE PRODUCTS REGULATORY AGENCY (MHRA)

� assess and, where appropriate evidence exists, authorise medical prod-ucts for sale and supply in UK;

� oversee the Notified Bodies that audit medical device manufacturers;� operate a quality surveillance system to sample and test medicines

– to address quality defects– to monitor the safety and quality of unlicensed products– investigate internet sales and potential counterfeiting of medicines

� regulate clinical trials of medicines and medical devices;� monitor and ensure compliance with statutory obligations relating to

medicines and medical devices;� promote safe use of medicines and devices;� manage the

The MHRA also hosts and supports a number of expert advisory bodies,including the Commission on Human Medicines (which replaced the Com-mittee on the Safety of Medicines in 2005), and the British PharmacopoeiaCommission. In addition, as part of the European system of medicinesapproval, the MHRA or other national bodies may be the Rapporteuror Co-rapporteur for any given pharmaceutical application, taking on thebulk of the verification work on behalf of all members, while the documentsare still sent to other members as and where requested.

Inspection and Standards Division

The MHRA’s Inspection and Standards Division is responsible for ensuringcompliance with the regulations and standards that apply to the manufac-ture, control and supply of medicines on the UK market.

Inspectorate

The Inspectorate Group in the MHRA’s Inspection and Standards Divisionis comprised of dedicated units for Good Manufacturing Practice (GMP),Good Distribution Practice (GDP), Good Laboratory Practice (GLP), GoodClinical Practice (GCP) and Good Pharmacovigilance Practice (GPvP).

Good Manufacturing Practice (GMP)

GMP Inspectors conduct inspections of pharmaceutical manufacturersand other organisations to assess compliance with EC guidance on GoodManufacturing Practice and the relevant details contained in marketingauthorisationsandClinicalTrialsAuthorisations (InvestigationalMedicinalProducts). They ensure that medicines supplied in the UK meet consistent

GPRD and British Pharmacopoeia.

1 MHRA: Licensing, Inspection and Enforcement for Human Medicines 5

II

high standards of quality, safety and efficacy. Overseas sites to be namedas manufacturing sites for products on UK marketing authorisations arealso required to pass an inspection prior to approval of the marketingauthorisation application.

GMP Inspectors are also responsible for inspecting and authorisingblood product establishments, biologicals products, investigational medi-cinal products, NHS manufacturing units and a range of manufacturingsites for active pharmaceutical ingredients. GMP Inspectors serve on anumber of UK, EU and PIC/S technical and standards committees and pro-vide help and advice to senior managers, Ministers and colleagues acrossthe agency, as necessary.

Good Distribution Practice (GDP)

GDP Inspectors conduct inspections of sites used by wholesale deal-ers for the storage and distribution of medicinal products. Inspectionsare undertaken against the requirements of the Medicines for HumanUse (Manufacturing and Wholesale Dealing and Miscellaneous Amend-ments) Regulations 2005 as well as the detailed guidelines contained inthe EC Guide on Good Distribution Practice for Medicinal Products forHuman Use.

Good Laboratory Practice (GLP)

GLP Inspectors conduct inspections of facilities that carry out non-clinicalstudies for submission to regulatory authorities to assess the safety ofnew chemicals to humans, animals and the environment. These inspec-tions assure the integrity of the data being submitted. The range of testfacilities to be monitored include those involved in the testing of humanand veterinary pharmaceuticals, agrochemicals, cosmetics, food and feedadditives and industrial chemicals.

Good Clinical Practice (GCP)

GCP Inspectors assess compliance with the requirements of Europeanguidelines and regulations relating to clinical trials by conducting inspec-tions at the sites of pharmaceutical sponsor companies, contract researchorganisations, academic research organisations, investigational trial sites,clinical trial laboratories and non-commercial clinical trial sites.

Good Pharmacovigilance Practice (GPvP)

By conducting inspections at the sites of marketing authorisation holdersPharmacovigilance Inspectors assess compliance with the requirements of


European legislation and guidelines relating to the process of monitoringmedicines post marketing for safety in clinical practice.

Licensing Office

Manufacture of and wholesale dealing in medicinal products are licensableactivities under UK and EU legislation. Applications for new licences andvariations to existing licences are processed by the Licensing Office in theInspection and Standards Division at Market Towers. Licensing Office staffmake extensive use of computer technology to carry out their work, whichdeals with a range of licences and covers activities including pharmaceuti-cal manufacturing (including the manufacture of investigational medicinalproducts) pharmaceutical wholesaling, authorisation of blood establish-ments and administrative tasks for clinical trials and pharmacovigilance.Licensing Office staff are also responsible for issuing certificates in supportof the World Health Organization scheme on the quality of pharmaceuti-cal products moving in international commerce (often referred to as exportcertificates). When carrying out their role, staff in the Licensing Office workclosely with colleagues in the Inspectorate.

Defective Medicines Report Centre (DMRC)

Manufacturers and importers are obliged to report to the Licensing Author-ity (MHRA) any quality defect in a medicinal product which couldresult in a recall or restriction on supply. Other users and distributorsof medicinal products are encouraged to do this. The MHRA’s Inspec-tion and Standards Division operates a Defective Medicines Report Centre(DMRC) to receive reports on products for human use and to co-ordinatethe necessary assessment and action. (The Veterinary Medicines Direc-torate operates a comparable system in relation to veterinary medicinalproducts.)

Where a defect is considered to be a risk to public health, the mar-keting authorisation holder withdraws the affected product from use andthe MHRA issues a “drug alert” letter. This alert is classified from 1 to4 depending upon the risk presented to the public health by the defec-tive product. Class 1 is the most critical, for example serious mislabelling,microbial contamination or incorrect ingredients, and requires immediaterecall; Class 4 is the least critical and advises “caution in use”.

The DMRC is also part of the European Rapid Alert System, whichdisseminates information on drug quality issues within EU MemberStates.

1 MHRA: Licensing, Inspection and Enforcement for Human Medicines 7

II

Enforcement and Intelligence Group

The Enforcement and Intelligence (E&I) Group investigates any reportedbreach of medicines legislation. The Agency’s primary objective is to ensurethat companies and individuals within the pharmaceutical industry complywith regulatory requirements. Enforcement officers have powers conferredby the Medicines Act 1968 and from regulations flowing from the Act.These include rights of entry, powers of inspection, seizure, sampling andproduction of documents. Officers investigate cases and, where appropri-ate, bring criminal prosecutions. MHRA investigators may also investigateoffences under other legislation such as the Theft Act, Trademarks Act andthe Offences Against the Person Act.

The aim of the Intelligence Unit is to drive forward the implementa-tion of intelligence-led enforcement and enable a more proactive approachto the acquisition and development of information. The Unit acts as aco-ordination point for all information-gathering activities and works inconjunction with a wide network of public and professional bodies andtrade associations, e.g. HM Revenue and Customs, Department of Health,Trading Standards and Port Health Authorities; the Police Service; and pro-fessional organisations such as the Royal Pharmaceutical Society, GeneralMedical Council and the Association of the British Pharmaceutical Indus-try (ABPI). Additionally, there is a network of other regulatory agenciesand law enforcement bodies within the European Community and in othercountries through which the E&I Group can exchange information andfollow trends in pharmaceutical crime. The E&I Group provides supportto the investigation teams, as well as monitoring trends and acting as aliaison point for outside organisations.

The E&I Group monitors trends in pharmaceutical crime and co-ordinates initiatives to counteract criminal activity. In particular, theavailability of counterfeit medicines is a key priority area and an anti-counterfeiting strategy has been agreed and implemented.

Advice

The MHRA publishes a series of Guidance Notes relating to its statu-tory functions. Those of particular interest to manufacturers and wholesaledealers include:

GN 5 Manufacturer’s LicencesGN 6 Wholesale Dealer’s LicencesGN 8 Borderline ProductsGN 14 Supply of unlicensed relevant medicinal products “Specials”.


These Guidance Notes and a list of others available may be obtained fromthe MHRA’s website or from the Agency’s Central Enquiry Point.

Contact details are as follows:

Address:Information Centre, 10-2 Market Towers, 1 Nine Elms Lane, London,SW8 5NQ, UK.Telephone: +44 (0)20 7084 2000 (weekdays 0900–1700)Telephone: +44 (0)20 7210 3000 (other times)Fax: +44 (0)20 7084 2353E-mail: [email protected]: www.mhra.gov.uk

SECTION

II

GUIDANCE ONGOODMANUFACTURINGPRACTICE (GMP)

The MHRA Index to the EUGuide to GMP

Locators indicate chapter and paragraph numbers.A = annex; Ch. = chapter; Gls. = glossary; PII = Part II of EC Guide

Acceptance criteria Ch. 6, GlsActive Pharmaceutical Ingredients (API) PII, Gls.

Agents, Brokers, Traders, Distributors, Repackers and RelabellersPII.17

Buildings and Facilities PII.4Change Control PII.13Complaints and Recalls PII.15Contract Manufacturers (including Laboratories) PII.16Documentation and Records PII.19Laboratory Controls PII.11Manufactured by Cell Culture/Fermentation PII.18Materials Management PII.7Medicinal Gases A6.5.2.1Packaging and Identification Labelling PII.9Personnel PII.3Process Equipment PII.5Production and In-Process Controls PII.8Quality Management PII.2Rejection and Reuse of Materials PII.14Starting Materials PII.1.3, Gls.Storage and Distribution PII.10Use in Clinical Trials PII.19Validation PII.12

Aerosol Products for Inhalation A10General A10.1Premises and Equipment A10.2–A10.3Production and Quality Control A10.4–A10.9

Agents PII.17Air Filtration A1.1, A1.29, A1.69, A5.11Air Grades

Biological Products A2.6

11

12 II GUIDANCE ON GOOD MANUFACTURING PRACTICE (GMP)

Immunological Veterinary Products A5.9Isolators A1.7Pressurised Aerosols for Inhalation A10.3Protective Clothing and A1.19–A1.20Sterile Products A1.3, A1.11–A1.12, A3.4, A4.10

Air-locks A1.27–A1.28, A5.11, Gls.Air Supply Systems Ch. 3.12, 5.19

Active Pharmaceutical Ingredients PII.4.20–PII.4.22Biological Products A2.13–A2.14Immunological Veterinary Products A5.11–A5.12Radiopharmaceuticals A3.3–A3.5Sterile Products A1.29–A1.31

Air Vent Filters A1.85, A2.17, A5.11Analysis, See TestingAncillary Areas Ch. 3.30–3.33Animals

Housing and Care Ch. 3.33, A2.21–A2.22, A5.18, A5.28–A5.31Quality Control Testing 6.22, A2.21

Aseptic Processing A1.12, A2.13, A13.7Audit

Independent Ch. 9.2, A13.3Internal (Self Inspection) Ch. 9, A13.3, PII.2.4Trail A11.10

Bacillus anthracis A2.9Backing-up, Electronic Data A11.14Batch (lot) Gls.

Bulk production Gls.Finished product Gls.Number Gls.Process Validation A15.25–A15.27, A15.34–A15.35

Batch Processing Mode, Gamma Irradiation A12, A12.36, A12.38Batch Records

Active Pharmaceutical Ingredients PII.6.5, PII.6.7Blood and Plasma Products A14.12–A14.15Immunological Veterinary Products A5.51Investigational Medicinal Products A13.9–A13.10, A13.21Irradiated Products A12.44Medicinal Gases A6.5.2.7, A6.5.2.12Packaging Ch. 4.18Processing Ch. 4.17Retention Ch. 6.8Review PII.6.7Sterile Products A1.61, A1.79–A1.80

Batch Release Ch. 1.2, Ch. 1.4, Ch. 4.24, A16Computerised Systems A11.19


I II I

Imported Products A16.6Investigational Medicinal Products A13.35, A13.42Medicinal Gases A6.7Products from Country with Mutual Recognition Agreement (MRA)

A16.7Products Manufactured in EC/EEA A16.5See also Parametric Release

BCG vaccine A2.4, A2.8Beta irradiation, see Electron Beam IrradiationBioburden Gls.Biogenerator Gls.Biological Agents Gls.

Containment A5.7–A5.20Contamination of Personnel A5.3–A5.5Handling A5.56

Biological Indicators A1.59, A1.63, A1.72, A1.79Biological Medicinal Products A2

Animal Quarters and Care A2.21–A2.22Documentation A2.23–A2.24Personnel A2.1–A2.5, A2.32Premises and Equipment A2.6–A2.20Production A2.25–A2.40Quality Control A2.41–A2.44

Biotechnological Processes PII.18.10–PII.18.11Blending Procedures A2.36, A5.46, PII.8.4Blinding Gls.

Operations A13.30–A13.31Blood and Plasma Products A14

Collection A14.9–A14.13Disposal of Rejected A14.26Premises and Equipment A14.6–A14.8Production and Quality Control A14.16–A14.24Quality Management A14.1–A14.5Retention of Samples A14.25Traceability and Post Collection Measures A14.14–A14.15

Blood Components Gls.Blow/Fill/Seal Technology A1.10Blowing Down Gls.Brokers PII.17Buildings, See PremisesBulk Gas Gls. (A6)Bulk Production Batch Gls. (A6)Bulk Products Gls.

Medicinal Gases A6.5.2Processing Operations 5.35–5.39


Receipt 5.6Specifications 4.12, A2.24

Calibration PII.5.3, Gls.Campaign Working Ch. 3.6, Ch. 5.19

Biological Products A2.10Investigational Medicinal Products A13.5Veterinary Medical Products A4.5, A4.7

Cell Banks A2.27–A2.33, A5.40–A5.45, Gls.Maintenance and Record Keeping PII.18.2

Cell Culture A2, PII.18, Gls.Harvesting, Isolation and Purification PII.18.4Viral Removal/Inactivation PII.18.5

Centrifugation A2.36, A5.46Certificate of Analysis PII.7.30–PII.7.32, PII.9.43, PII.11.4Certification

Finished Product Batch Gls.by Qualified Person A16

Change Control A15.43–A15.44, Gls.Active Pharmaceutical Ingredients PII.13, PII.19.7

Chemical Indicators A1.63Chromatography Equipment A2.40Clean Areas A1.1–A1.6, Gls.

Blood and Plasma Products A14.22Classification A1.3Equipment A1.32–A1.36Immunological Veterinary Products A5.8, A5.10–A5.20Personnel A1.13–A1.21, A1.45Premises A1.22–A1.31Sanitation A1.37–A1.39Transfer Operations A1.53, A5.48–A5.54See also Sterile Products

Clean/Contained Area Gls.Cleaning

Clean Area Clothing A1.21Clean Areas A1.37–A1.39Containers and Valves for Aerosols A10.6Design of Premises and Ch. 3.9–3.11, A1.17–A1.21, A2.15Equipment Ch. 3.36, Ch. 5.19, A2.15, PII.5.2Gas Equipment/Pipelines A6.5.3.4Investigational Medicinal Products A13.6, A13.26Records PII.6.2Validation A15.36–A15.42, PII.12.7, Gls.

Clinical trials Gls.Active Pharmaceutical Ingredients for PII.19Products for, See Investigational Medicinal Products


I II I

Closed Systems Ch. 5.19, A2.11Clostridium botulinum A2.9Clostridium tetani A2.9Clothing 2.15, 5.19, PII.3.21

Animal Quarters A2.22Changing Facilities Ch. 3.31, A1.27, A2.22, A5.11–A5.12Contained/Clean Areas A1.17–A1.21, A5.4–A5.5

Commissioning, Radiation Treatment Plant A12.12–A12.27Comparator Products A13.27–A13.28, Gls.Complaints Ch. 8.1–8.7

Active Pharmaceutical Ingredients PII.15, PII.17.7Investigational Medicinal Products A13.38

Compressed Gas Gls.Computer System Gls.Computerised Systems Ch. 4.9, A11, Gls.

Active Pharmaceutical Ingredients PII.5.4Personnel A11.1Validation A11.2

Concurrent Validation A15.28–A15.30, Gls.Confirmation Gls.Consultants PII.3.3Contained Areas Gls.

Premises A5.7, A5.10–A5.20Transfer Operations A5.48–A5.54

ContainersActive Pharmaceutical Ingredients PII.8.11, PII.9.46Blow/Fill/Seal A1.10Cleanliness Ch. 5.48Damaged Ch. 5.4Immunological Veterinary Products A5.60–A5.63Medicinal Gases A6.5.3.2, Gls.Sample Ch. 6.13Starting Materials Ch. 5.27, Ch. 5.30Sterile Products A1.88–A1.90Veterinary Medicinal Products A4.9See also Cryogenic Vessels; Cylinders; Packaging

Containment Gls.Active Pharmaceutical Ingredients PII.4.4Biological Products for Human Use A2.18Immunological Veterinary Products A5.7–A5.8, A5.10–A5.20

Contamination Gls.See also Cross-contamination

Contamination Control Ch. 3.1, Ch. 5.10Active Pharmaceutical Ingredients PII.4.13, PII.4.21–PII.4.22, PII4.72,

PII.8.5


Blood and Plasma Products A14.8, A14.22–A14.24Cell Culture/Fermentation PII.18.15, PII.18.36Immunological Veterinary Products A5.5Investigational Medicinal Products A13.5Sterile Medicinal Products A1.40–A1.54

Continuous Cultures A2.44, A5.68Continuous Processing Mode, Gamma Irradiation A12, A12.35,

A12.37Contract Manufacturer Gls.Contracted-out Operations

Active Pharmaceutical Ingredients PII.16Analysis Ch. 6.6, Ch. 7, PII.16Computerised Systems A11.18Finished Product Batch Release A16.5.3Investigational Medicinal Products A13.41Manufacturing Ch. 7Radiation Treatment A12.1–A12.2, A12.11

Controlled Areas Gls.Conveyor belts A1.32Cooling, Sterile A1.65Creams A9

Premises and Equipment A9.1–A9.3Production A9.4–A9.9Sterile A1.11, A1.12

Critical Gls.Cross-contamination Gls.

Active Pharmaceutical Ingredients PII.4.21–PII.4.22, PII.4.42,PII.7.22

Biological Products A2.7Immunological Veterinary Products A5.5in Production Ch. 3.6, Ch. 5.18–5.20Veterinary Medicinal Products A4.2, A4.6

Crude plant (vegetable drug) A7, Gls.Cryogenic Gas Gls.Cryogenic Vessels Gls.

Checks Before Filling A6.5.3.6Filling A6.6.10–A6.6.11

Culture media 6.20, A2.34, PII.18.35Cylinder Bundle Gls.Cylinders A6.5.3.2, Gls.

Filling A6.3.2.2, A6.3.2.4, A6.5.3Labelling A6.5.3.9Preparation for Filling A6.5.3.4–A6.5.3.7Segregation A6.3.1.3


I II I

Storage A6.7Decontamination 5.19, A2.5, A2.15, A5.5, A5.47Dedicated Facilities 3.6

Active Pharmaceutical Ingredients PII.4, PII.19.3Biological Medicinal Products A2.7–A2.9Blood and Plasma Products A14.6Immunological Veterinary Products A5.14Radiopharmaceuticals A3.2

Design Qualification A15.9–A15.10, Gls.Destruction, Unused Investigational Products A13.53–A13.55Deviation Gls.Disinfectants A1.37–A1.39Disinfection A5.16, A5.32, A5.51Dispatch Gls.Distribution

Active Pharmaceutical Ingredients PII.10.2Investigational Medicinal Products A13.43–A13.47Radiopharmaceuticals A3.10Records 4.25, 8.12

Distributors PII.17Documentation Ch. 4

Active Pharmaceutical Ingredients PII.6, PII.19.9Biological Medicinal Products A2.23–A2.24Blood and Plasma Products A14.10–A14.15Contained/Clean Areas A5.20General Ch. 4.1–4.9Herbal Products A7.5–A7.6Investigational Medicinal Products A13.6–A13.11Medical Gases A6.4Qualification and Validation A15.6–A15.8Quality Control Ch. 6.7–6.10Radiation Treatment A12.42–A12.45Required Ch. 4.10–4.29Validation A15.6–A15.8, PII.12.2See also Records

Dose Mapping A12.10Electron Beam Irradiation A12.25–A12.26Gamma Irradiation A12.17–A12.22

DosimetryRadiation Sterilisation A1.71Radiation Treatment A12.4–A12.8, A12.10

Drains 3.11, A1.26, PII.4.24Drug Product, See Medicinal ProductDrug Substance, See Active Pharmaceutical Ingredients


Dust Ch. 3.14, 5.11, A4.1, A7.4Eating Ch. 2.17, PII.3.23Ectoparasiticides A4.5–A4.6Effluents A2.19, A5.11, A5.32, A5.52Electron Beam Irradiation A12

Design A12.23–A12.24Dose Mapping A12.25–A12.26Processing A12.40–A12.41

Electronic Data Processing Systems Ch. 4.9, A11Emulsions, Sterile A1.11, A1.12Equipment Ch. 3.34–3.44

Active Pharmaceutical Ingredients PII.8.5, PII.19.3Biological Products A2.6–A2.20Blood and Plasma Products A14.6–A14.8Chromatography A2.40Cleaning Ch. 3.36, Ch. 5.19, A2.15, PII.5.2Cleaning and Use Record PII.6.2Contained/Clean Areas A5.11–A5.12, A5.17, A5.21–A5.27Investigational Medicinal Products A13.5–A13.7Liquids, Creams and Ointments A9.1–A9.3Log Books 4.28–4.29Maintenance 3.35, A1.34, A1.36, A5.26, PII.5.2Medicinal Gases A6.3.2Operating Procedures 4.27Pressurised Aerosols for Inhalation A10.2–A10.3Radiopharmaceuticals A3.2–A3.5Sterile Products A1.32–A1.36

Ethylene Oxide Sterilisation A1.76–A1.81Evacuate Gls.Exotic Organisms Gls.Expiry (Expiration) Date PII.9.43, PII.11.6, PII.11.41, Gls.Facilities, Dedicated, See Dedicated FacilitiesFeedingstuffs, Medicated A4.1–A4.4Fermentation PII.18

Classical PII.18.12Harvesting, Isolation and Purification PII.18.4Viral Removal/Inactivation PII.18.5

Fermenters A2.35, A5.50Filling

Cryogenic Vessels A6.10–A6.11Gas Cylinders A6.3.2.2, A6.3.2.4, A6.5.3Pressurised Aerosols for Inhalation A10.1, A10.7–A10.8

Filling ProcessesImmunological Veterinary Products A5.60–A5.63


I II I

Liquids, Creams and Ointments A9.8Sterile Products A1.11, A1.12

FiltrationAir A1.1, A1.29, A1.69, A5.11Fluids for Pressurised Aerosols A10.5Infusion Fluids A1.52Sterilisation by A1.82–A1.87

Finished Product Batch Gls.Certification Gls.

Finished Products Ch. 5.58–5.60, Gls.Assessment Ch. 6.3Quarantine Ch. 5.5, 5.58Release, See Batch releaseRetention of Samples Ch. 6.14Specifications Ch. 4.13Sterile A1.88–A1.90

Food and Drink Ch. 2.17, PII.3.23Free Movement, Investigational Medical Products A13.39Freeze Driers A5.27Fumigation A1.39Gamma Irradiation A12

Design A12.14–A12.16Dose Mapping A12.17–A12.22Processing A12.35–A12.39

Garments, See ClothingGas(es) Gls.

Cylinders, See CylindersLiquefied A6.3.2.5, A6.5.2.10, Gls.Medicinal, See Medicinal Gases

Good Manufacturing Practice (GMP) Ch. 1.3Hand-washing Facilities Ch. 2.19, A1.27Heat Sterilisation A1.62–A1.65HEPA Air Filters A1.3, A1.69, A5.11Herbal Medicinal Products A7, Gls.

Documentation A7.5–A7.7Premises A7.1–A7.4Quality Control A7.8–A7.9Sampling A7.7

Holding, Active Pharmaceutical Ingredients PII.17.4Hydrostatic Pressure Test A6.5.3.6, A6.6.1, Gls.Hygiene Ch. 2.13–2.20, A1.16, PII.3.2Immunological Veterinary Medicinal Products A5

Animals and Animal Houses A5.28–A5.31Disinfection/Waste Disposal A5.32


Equipment A5.21–A5.27Personnel A5.1–A5.5, A5.45Premises A5.6–A5.20Production A5.33–A5.64Quality Control A5.36, A5.65–A5.68

Imported Products Ch. 2.4Certification and Batch Release A16.6–A16.7Country with Mutual Recognition Agreement (MRA) A16.7

Importer Gls.Impurity Gls.

Maximum Theoretical Residual Impurity Gls.Profile PII.11.21–PII.11.22, Gls.

In-process Controls Ch. 3.17, Ch. 6.18, Gls.Active Pharmaceutical Ingredients PII.8Biological Medicinal Products A2.41Immunological Veterinary Medicinal Products A5.65Medicinal Gases A6.5.2.4

Inactivated Products A5.57–A5.58Incoming Production Materials, See Starting MaterialsIncubators A5.25, A5.55Infected Gls.Infectious Diseases

Blood Donors A14.15Personnel Ch. 2.15, A2.3, A18.3.24Testing Blood and Plasma Products for A14.16, A14.18–A14.20See also Viruses

Information Transfer, Active Pharmaceutical Ingredients PII.17.6Infusion fluids A1.52Inhalation, Pressurised Aerosol Products for A10Inspection

Parenteral Products A1.90Self Ch. 9, PII.2.4

Installation Qualification A15.11–A15.12, Gls.Intermediate Products Gls.

Active Pharmaceutical Ingredients PII.6.3, PII.8.2Biological Medicinal Products A2.41Blending PII.8.4Immunological Veterinary Medicinal Products A5.66Packaging and Labelling PII.9Processing Operations Ch. 5.35–5.39Receipt Ch. 5.6Specifications Ch. 4.12, A2.24Testing PII.11.2See also Starting Materials


I II I

Investigational Medicinal Products A13, Gls.Batch Release A13.38Blinding Operations A13.21 Gls.Comparator Products A13.19, Gls.Complaints A13.48Destruction A13.49–A13.51, A13.53–A13.55Documentation A13.6–A13.7Labelling A13.26–A13.34Manufacturing Formulae and Processing Instructions A13.10Order A13.8, GlsPackaging A13.16, A13.23–A13.25Personnel A13.3Premises and Equipment A13.5Product Specification File A13.9, Gls.Production A13.15–A13.33Quality Control A13.34–A13.37Quality Management A13.1–A13.2Randomisation Code A13.22Recalls A13.49Returns A13.51–A13.52Shipping A13.43–A13.47, Gls.Transfers Between Sites A13.47

Investigator Gls.Irradiation, See Radiation TreatmentIsolator Technology A1.7–A1.9Jewellery A1.18Key Personnel Ch. 2.2.3–2.7Labelling Ch. 5.12–5.13, 5.49–5.53

Active Pharmaceutical Ingredients PII.6.3, PII.9Blood and Plasma Products A14.21Gas Cylinders A6.5.3.9Investigational Medicinal Products A13.17–A13.20Pipework Ch. 3.42Sample Containers Ch. 6.13Starting Materials Ch. 5.29Sterile Products A1.60

Laboratory(ies)Contract Ch. 6.6, Ch. 7, PII.16Control Records PII.6.6Controls PII.11, PII.19.8Facilities Ch. 3.26–3.29, PII.4.15Good Practice Ch. 6.5–6.22Reagents Ch. 6.19–6.21See also Quality Control; Testing


Laminar Air Flow Systems A1.3Leak Tests

Autoclaves A1.66Gas Cylinders A6.6.9Isolators A1.9Pressurised Aerosol Products A10.9

Lighting Ch. 3.16, PII.4.5Liquefiable Gases Gls.Liquefied Gases A6.3.2.5, A6.5.2.10, Gls.Liquids A9

Premises and Equipment A9.1–A9.3Production A9.4–A9.9

Log Books, Equipment Ch. 4.28–4.29Lot, See BatchLubricants PII.5.14Maintenance

Cell banks PII.18.2Equipment Ch. 3.34, A1.34, A1.36, A5.26Premises Ch. 3.2, A18.4.7Workshops Ch. 3.32

Make-up A1.18Manifolds A6.3.2.2, A6.5.3.3, A6.6.4, Gls.Manufacture Gls.Manufacturer Gls.Manufacturing Formulae Ch. 4.1, 4.14

Investigational Medicinal Products A13.14Master Production and Control Records PII.6.4Materials Gls.

Management, Active Pharmaceutical Ingredients PII.7Recovery PII.14.4See also Intermediate Products; Starting Materials

MediaImmunological Veterinary Products A5.38–A5.39Sterilisation A2.37, A5.39

Medical Examinations Ch. 2.14, A5.3Medicated Feedingstuffs A4.1–A4.4Medicinal Gases A6, Gls.

Documentation A6.4Liquefied A6.3.2.5, A6.5.2.10, Gls.Personnel A6.2Premises and Equipment A6.3Production A6.5Quality Control A6.6Storage/Release A6.7


I II I

See also CylindersMedicinal Plants A7, Gls.Medicinal Product Gls.Microbial Cultures A2Microbiological Monitoring

Active Pharmaceutical Ingredients PII.11.23Clean Areas A1.5–A1.6Radiation Treatment A12.46

Monoclonal Antibodies A2, A2.11Mother Liquor Gls.Mutual Recognition Agreement (MRA) A16.7, Gls.Ointments A9

Premises and Equipment A9.1–A9.3Production A9.4–A9.9Sterile A1.11, A1.12

One-shot Filling Process A10.1Open Lesions (Body Surface) Ch. 2.15, PII.3.24Operational Qualification A15.13–A15.15, Gls.Order Gls.

Investigational Medicinal Products A13.8Packaging Gls.

Active Pharmaceutical Ingredients PII.9Batch Records Ch. 4.18, A13.13–A13.14Instructions Ch. 4.1, Ch. 4.16, A13.12Investigational Medicinal Products A13.12–A13.14, A13.23–A13.25Operations Ch. 5.44–5.57Premises Ch. 3.15

Packaging Materials Ch. 5.40–5.43, Gls.Active Pharmaceutical Ingredients PII.6.3, PII.9.2Printed Ch. 5.41, Ch. 5.50–5.53Sampling A8Specifications Ch. 4.11Storage Ch. 3.25, Ch. 5.41

Parametric Release A17Definition A17.1.1, A17.4Sterile Products A17.3

Parenteral Solutions A1.90Penicillins, Veterinary Products Containing A4.7Performance Qualification A15.16–A15.18, Gls.Personnel Ch. 2

Active Pharmaceutical Ingredients PII18.3Authorised, Data Entry/Amendment A11.8, A11.10Biological Medicinal Products A2.1–A2.5, A2.32Clean Areas A1.13–A1.21, A1.45


Computerised Systems A11.1General Ch. 2.1Hygiene Ch. 2.13–2.20, A1.16, PII.3.2Immunological Veterinary Products A5.1–A5.5, A5.45Investigational Medicinal Products A13.4Key Ch. 2.3–2.7Medicinal Gases A6.2Principle Ch. 2Qualifications PII.3.1Radiopharmaceuticals A3.1Restricted Access Ch. 2.11, Ch. 3.5, Ch. 5.16, A5.19Sampling A8.1Training, See Training, Personnel

Pest Control A4.1Pipes/Pipelines A1.25, A2.17, PII.4.23

Connections 5.14, A6.3.2.2Labelling Ch. 3.42Water Ch. 3.43

Planning, Validation A15.2–A15.5Plants, Medicinal A7, Gls.Plasma Products, See Blood and Plasma ProductsPremises Ch. 3

Active Pharmaceutical Ingredients PII.18.4Biological Medicinal Products A2.6–A2.20Blood and Plasma Products A14.6–A14.8General Ch. 3.1–3.5Herbal Products A7.1–A7.4Immunological Veterinary Products A5.6–A5.20Investigational Medicinal Products A13.5Liquids, Creams and Ointments A9.1–A9.3Medicinal Gases A6.3.1Pressurised Aerosols for Inhalation A10.2–A10.3Radiation Treatment A12.28Radiopharmaceuticals A3.2–A3.5Sterile Products A1.22–A1.31Veterinary Medicinal Products A4.1

Premixes for Medicated Feedingstuffs A4.1–A4.4Pressure Records, Autoclaves A1.66Pressurised Aerosol Products for Inhalation A10Printed Packaging Materials Ch. 5.41, Ch. 5.50–5.53Procedure Gls.Procedures Ch. 4.1, Ch. 4.19–4.29, Gls.

Complaints Ch. 8.2Deviations from Ch. 5.15Recalls Ch. 8.9


I II I

Process Aids Gls.Process Controls, See In-process ControlsProcess Validation A15.20–A15.35, PII.12.4, PII.12.5, Gls.Processing Instructions Ch. 4.1, Ch. 4.14–4.15

Active Pharmaceutical Ingredients PII.6.4Herbal Products A7.6Investigational Medicinal Products A13.10–A13.11

Processing Operations Ch. 5.35–5.39Active Pharmaceutical Ingredients PII.8.1Biological Products A2.10–A2.14, A2.34–A2.40Immunological Veterinary Products A5.46–A5.64Investigational Medicinal Products A13.16–A13.18Radiation Treatment A12.29–A12.41Sterile Products A1.40–A1.54

Product Specification File A13.9, Gls.Production Ch. 5, Gls.

Active Pharmaceutical Ingredients PII.8, PII.19.5Activities, Responsibility for PII.2.3Areas Ch. 3.6–3.17, 6.4Biological Medicinal Products A2.25–A2.40Blood and Plasma Products A14.16–A14.24Duties of Head of Department Ch. 2.5, Ch. 2.7General Ch. 5.1–5.17Herbal Products A7.4Immunological Veterinary Products A5.33–A5.64Instructions, See Processing InstructionsInvestigational Medicinal Products A13.15–A13.21Liquids, Creams and Ointments A9.4–A9.9Medicinal Gases A6.5Pressurised Aerosols for Inhalation A10.4–A10.9Prevention of Cross-contamination Ch. 3.6, Ch. 5.18–5.20Radiopharmaceuticals A3.6–A3.7Validation Ch. 5.21–5.24, A1.42–A1.43, A1.54, A2.38, A5.59

Prospective Validation A15.24–A15.27, Gls.Purge Gls.Purification, from Cell Culture/Fermentation Systems PII.18.4Qualification A15.9–A15.19, Gls.

Active Pharmaceutical Ingredients PII.12.3Design A15.9–A15.10, Gls.Documentation A15.6–A15.8Established (In-Use) Facilities, Systems and Equipment A15.19Installation A15.11–A15.12, Gls.Operational A15.13–A15.15, Gls.Performance A15.16–A15.18, Gls.

Qualification and Validation A15


Qualified Person (QP) Gls.Batch Release Ch. 4.24, A11.19, A16Certification by A16Complaints Ch. 8.1Contract Manufacture and Analysis Ch. 7.11Duties Ch. 2.4, A3.8, A16.8Medicinal Gases A6.2.2.1Recalls Ch. 8.8

Quality Assurance Ch. 1.2, Ch. 2.12, Gls.Active Pharmaceutical Ingredients PII.2.13Blood and Plasma Products A14.1Investigational Medicinal Products A13.1–A13.2

Quality Control Ch. 6, Gls.Active Pharmaceutical Ingredients PII.2.13, PII.19.2Areas Ch. 3.26–Ch. 3.29Basic Requirements Ch. 1.4Biological Medicinal Products A2.41–A2.44Blood and Plasma Products A14.16–A14.24Complaints Ch. 8.3Definition Ch. 1.4Documentation Ch. 6.7–6.10Duties of Head of Department Ch. 2.6, Ch. 2.7General Ch. 6.1–6.4Good Laboratory Practice Ch. 6.5–6.22Herbal Products A7.8–A7.9Immunological Veterinary Products A5.35–A5.36, A5.65–A5.68Investigational Medicinal Products A13.34–A13.37Medicinal Gases A6.6Pressurised Aerosols for Inhalation A10.4–A10.9Radiopharmaceuticals A3.8–A3.9Sampling Ch. 6.11–6.14Sterile Products A1.91–A1.93Testing A2.21, Ch. 6.15–6.22

Quality Management Ch. 1Active Pharmaceutical Ingredients PII.2, PII.17.3Blood and Plasma Products A14.1–A14.5Investigational Medicinal Products A13.1–A13.2

Quality Review, Active Pharmaceutical Ingredients PII.2.5Quality Unit PII.2.13, PII.2.20–PII.2.22, PII.11.10, PII.19.21, Gls.Quarantine Ch. 3.21, Ch. 5.5, Gls.

Active Pharmaceutical Ingredients PII.7.2Finished Products Ch. 5.5, Ch. 5.58Medicinal Gases A6.7.1

Radiation Indicators A1.74, A12.31


I II I

Radiation Sterilisation A1.70–A1.75Radiation Treatment A12

Commissioning of Plant A12.12–A12.27Documentation A12.42–A12.45Dosimetry A12.4–A12.8Microbiological Monitoring A12.46Premises A12.28Process Validation A12.9–A12.11Processing A12.29–A12.41Responsibilities A12.1–A12.3

Radiopharmaceuticals A3, Gls.Distribution and Recalls A3.10Personnel A3.1Premises and Equipment A3.2–A3.5Production A3.6–A3.7Quality Control A3.8–A3.9

Randomisation Code A13.22Raw Materials Gls.

Active Pharmaceutical Ingredients PII.6.3, PII.19.4See also Starting Materials

Re-commissioning, Radiation Treatment Plant A12.27Re-evaluation, Materials PII.7.5Re-validation Ch. 5.24, A1.54, A1.56, A15.45, (Gls.)Reagents, Laboratory Ch. 6.19–6.21Recalls Ch. 3.23, Ch. 8.8–8.15

Active Pharmaceutical Ingredients PII.15, PII.17.7Investigational Medicinal Products A13.49–A13.50Radiopharmaceuticals A3.10

ReceiptsIncoming Materials Ch. 5.3, Ch. 5.5–5.6, PII.7.2Procedures and Records Ch. 4.19–4.21

Recombinant DNA Technology, Products of A2, A2.11, PII.18.11Reconciliations Ch. 1.3, Ch. 1.4, Ch. 5.8, Ch. 5.56, Ch. 6.3, Ch. 8.14, Gls.

Immunological Veterinary Products A5.64Investigational Medicinal Products A13.12, A13.24Irradiated Products A12.42

Records Ch. 4.1, Ch. 4.19–4.29Active Pharmaceutical Ingredients PII.6Batch, See Batch RecordsCell Banks PII.18.2Complaints Ch. 8.5–8.6Contract Manufacture Ch. 7.13Distribution Ch. 4.25, Ch. 8.12Quality Control Tests Ch. 6.17


Self Inspections Ch. 9.3See also Documentation

Recovery Ch. 5.61–5.65, Gls.Materials and Solvents PII.14.4

Reference Samples, See Samples, ReferenceReference Standards

Primary PII.11.17–PII.11.18, Gls.Secondary PII.11.19, Gls.

Refreshment Rooms Ch. 3.30Refuse PII.4.6Rejected Materials Ch. 3.23, Ch. 5.61–5.65

Active Pharmaceutical Ingredients PII.14.1Blood and Plasma Products A14.26Procedures Ch. 4.24Reprocessing, See Reprocessing

Relabellers PII.17Relabelling, Active Pharmaceutical Ingredients PII.17.4Release of Finished Products, See Batch ReleaseRepackaging, Active Pharmaceutical Ingredients PII.17.4Repackers PII.17Reprocessing Ch. 5.62–5.64, Gls.

Active Pharmaceutical Ingredients PII.14.2Reserve Samples, See Samples, ReferenceRest Rooms Ch. 3.30Retention of Samples Ch. 6.14

Active Pharmaceutical Ingredients PII.11.7Biological Medicinal Products A2.42Blood and Plasma Products A14.25Immunological Veterinary Products A5.66Investigational Medicinal Products A13.36Medicinal Gases A6.6.12Veterinary Medical Products A4.8–A4.9

Retest Date PII.9.43, PII.11.6, PII.11.41, Gls.Retrospective Validation A15.31–A15.35, Gls.Returns Ch. 3.23, Ch. 5.61–5.65, Gls.

Active Pharmaceutical Ingredients PII.14.5, PII.17.8Investigational Medicinal Products A13.51–A13.52

Reworking PII.14.3, Gls.Risk Analysis Gls.Risks

Cross-Contamination Ch. 3.1, Ch. 3.6, Ch. 3.8, Ch. 3.17, Ch. 3.38,Ch. 5.9, Ch. 5.18, Ch. 5.19 (c), (d), Ch. 5.44

Equipment/Premises Design Ch. 3 (Principle), Ch. 3.1, Ch. 3.6, Ch. 3.38,Ch. 5.9


I II I

Quality Ch. 1Distribution 1.3 (xiv)Patient Ch. 1 (Principle)Personnel Responsibilities Ch. 2.1

Reprocessing Ch. 5.62Recovery of Batches Ch. 5.63Stability Testing Frequency Ch. 6.29

SamplesActive Pharmaceutical Ingredients PII.11.7Batch Packaging Materials Ch. 4.18(g)Bulk Starting Materials Ch. 5.30Contract Acceptor Ch. 7.12Imported Products Testing A16.6–A16.7Labelling Ch. 6.13Quality Control Ch. 1.4(ii), Ch. 4.22

Biologicals, intermediates A2.42Immunological veterinary medicinal products A5.66

Radiopharmaceuticals A3.9Recalls and medical samples Ch. 8.12Reference/Retention Ch. 1.4(viii), Ch. 6.12, Ch. 6.2, A19, Ch. 7.13Retention, see Retention of Samples, A19See also SamplingShared Responsibility for Ch. 2.7Special Laboratory Requirements Ch. 3.29Sterile Products A1.88, A1.93,Storage Ch. 3.27Veterinary Medicinal Products A4.8–A4.9

Retained Samples A4.8–A4.9Sampling

Area Ch. 3.22, PII.4.14Aseptic Products, Methods of A1.5Avoidance of Cross Contamination during Ch. 3.14Biological Products A2.35Clean Areas A1.5Cleaning Validation PII.12.73Contracting Ch. 7.12Herbal Products A7.4, A7.7Imported Products A16.6, A16.7In-process controls Ch. 4.16(h), PII.8.3Medicinal Gases A6.5.2.11, A6.9Metered Dose Aerosols A10.4Multiple Batch Deliveries Ch. 5.28Packaging Materials A8Personnel A8.1


Ports, Fermenters A5.50Procedures and Records Ch. 4.1, Ch. 4.11(b), Ch. 4.22, Ch. 5.2, Ch. 6.7,

PII.6.41, PII.6.52, PII.6.60Qualified Person A16.8.1(e)Quality Control Ch. 1.4 et seq., Ch. 6 (Principle), Ch. 6.4, Ch. 6.11–6.14Starting Materials Ch. 3.22, 5.30, A8, PII.7Sterile Products A1.88, A1.93

SanitationActive Pharmaceutical Ingredients PII.4.7Clean Areas A1.37–A1.40Procedures and Records Ch. 4.26

SecurityComputerised System Ch. 4.26Data Ch. 4.9, A11.13, A11.14Randomisation Code A13.22

Seed Lots A2.27–A2.33, A5.40–A5.45, Gls.Self Inspection Ch. 9, PII.2.4

Review of Technical Agreements Ch. 1.5(xii)Sewage PII.4.6Shipping Gls.

Investigational Medicinal Products A13.40–A13.46See also Distribution and also Product Specification File

Signed (Signature) Gls.Signed

Batch Packaging Records Ch. 4.18Batch Processing Records Ch. 4.17Production Records Ch. 2.5(iii)Documents (general) Ch. 4.3, Ch. 4.7

Simulated Product Gls.Sinks and Drains in Clean Rooms A1.26Smoking Ch. 2.17, PII.3.23Software, Computerised Systems A11.5Solvents Gls.

Recovery PII.14.4Specifications Ch. 4.1, 4.10–4.13, Gls.

Approval of Ch. 2.6(iv)Active Pharmaceutical Ingredients PII.6.1, PII.11.12–PII.11.13Biological Medicinal Products A2.23–A2.24Contracts Ch. 7.5Documents Ch. 4.10 to Ch. 4.13, Ch. 6.7GMP Aspects Ch. 1.3(i)Irradiation Process A12.11Medicinal Gases A6.5.3.2, A6.6.2Metered Dose Aerosols A10.4


I II I

Packaging Material Ch. 4.16(d)PremisesProduct Quality Review Ch. 1.5Quality Control Ch. 1.4, Ch. 6 (Principle), Ch. 6.7, Ch. 6.17Reprocessing and Ch. 5.62Stability Programme Ch. 6.24Starting Materials Ch. 4.11, A1.46, A2.23, A5.26, A5.34, A7.5Testing Ch. 6.17Ventilation systems for immunological veterinary medicines A5.20

Spillages, Accidental A5.47Sponsor Gls.Stability Monitoring

Active Pharmaceutical Ingredients PII.11.5, PII.17.5Ongoing Stability Programme Ch. 6.29Product Quality Review Ch. 1.5(vii)

Starting Materials Ch. 5.25–5.34, Gls.Active Pharmaceutical Ingredients PII.1.1 and 1.2, Gls.Biological Medicinal Products A2.25–A2.26

Contamination levels and facilities A2.6Delivery Ch. 5.27–5.28Dispensing Ch. 5.32–5.34Health Status of Animals A2.22Herbal Products A7.5Identity Testing A8.2–A8.4Immunological Veterinary Products A5.33–A5.37Investigational Medicinal Products A13.6, A13.9Key Personnel Roles Ch. 2.6Labelling Ch. 5.29Manufacturing Documents C.4.14(c)Parametric Release A17.4(b)Procedures and Records Ch. 4.21Product Quality Review Ch. 1.5(i)Purchase Ch. 5.25–5.26Purchased Intermediates/ Bulks Ch. 5.6Quality Control Ch. 1.4(i, ii, viii), Ch. 5.31Records PII.6.3Reference and Retention of Samples Ch. 6.14, A19.2.1–A19.2.4,

A19.4.3, A19.7Sampling Ch. 3.22, 5.30, A8.2–A8.4, PII.7.3Specifications Ch. 4.1, Ch. 4.11, A2.23, A5.34, A7.5Sterile Handling A1.12Sterile Products

Microbiological quality A1.46Sterilisation A2.26, A5.37


Weighing Ch. 3.13See also Intermediate Products; Raw Materials

SteamAdverse effects on product stability A4.3Quality and Penetration A1.67–A1.68Sterilisation A1.66–A1.68, A1.82, A2.17, A5.24, A5.50

Sterile Process Design A1.57Sterile Products A1, A3.4, A4.10, A1.3

Aseptic Preparations A1.12Blow/Fill/Seal Technology A1.10Finishing A1.88–A1.90General A1.1–A1.6Isolator Technology A1.7–A1.9Parametric Release A17.3Personnel A1.13–A1.21Processing A1.40–A1.54Product Quality Review Ch. 1.5(xii)Quality Control A1.91–A1.93Sampling Ch. 6.11Terminally Sterilised A1.11See also Clean Areas

Sterilisation A1.55–A1.87Bioburden A1.52Chromatography Production Columns A2.40Disinfection/ Inactivation A5.59Dry Heat A1.69Equipment A1.32–A1.36, A2.17, A5.17, A5.22, A5.24, A5.27Ethylene Oxide A1.76–A1.81Filtration A1.82–A1.87Heat A1.62–A1.65In-place A1.10, A2.17Nutrient Media A1.42, A2.37, A5.39Precautions A1.40Process Records and QC A1.59–A1.93Radiation A1.70–A1.75Starting Materials A2.26, A5.37Steam A1.66–A1.68Time Constraints A1.50–A1.51Transfer Devices A1.7Validation A1.55–A1.58

Sterility Gls.Assurance System A17.4Testing A1.91, A1.93


I II I

Storage Ch. 5.7Active Pharmaceutical Ingredients PII.7.4, PII.10Ancillary Areas Ch. 3.31Areas Ch. 3.18–3.25Biological Agents, Intermediates or Products A5.25, A5.44, A5.63

A5.66Blood and Plasma Products A14.17Cell Banks and Seed Lots A2.33Equipment A1.36, A1.50GMP fundamentals Ch. 1.3Herbal Products A7.1–A7.3Immunological Veterinary Products A5.25, A5.63Key Personnel Responsibilities Ch. 2.7Labelling of Goods Ch. 5.29Laboratory Reagents and Standards Ch. 6.20–6.21Liquids, Creams and Ointments A9.5, A9.9Medicinal Gases A6.3.1.2, A6.5.2.10–A6.5.2.11, A6.7.1–A6.7.4Packaging Materials Ch. 3.25, Ch. 5.41Personnel Hygiene Ch. 2.17Premises Ch. 3.3, Ch. 3.5, Ch. 3.8, Ch. 3.18–Ch. 3.25,

Ch. 3.27Processing and Bulk Ch. 4.15(e)Procedures Ch. 4.21, Ch. 5.2Recalled Products Ch. 8.13Rejected Materials Ch. 5.61Returned Products Ch. 5.65Samples Ch. 6.11, A2.42Seed lots and cell banks A2.31–A2.33, A5.44–A5.45Specifications Ch. 4.11(d, e), Ch. 4.13(f, g)Stability Programme Ch. 6.24, Ch. 6.27Starting Materials Ch. 5.29Sterile Products A1.81Time Considerations In-Process A1.50, A1.51

Suspensions, Sterile A1.11, A1.12System Gls.

Closed (Minimising Cross-contamination) Ch. 5.19(f)Data Processing Ch. 4.9Documentation Ch. 4 (Principle), Ch. 4.5People and Quality Ch. 2 (Principle)Quality Assurance Ch. 1 (Principle), Ch. 1.2Quarantine Ch. 3.21Recall Ch. 1.3(xv), Ch. 8Stability Programme, pack closure Ch. 6.27


Tank Gls.Tanker Gls.Temperature

Premises Ch. 3.3, Ch. 3.12Processing Instructions Ch. 4.5(c)Production Ch. 3.12Records, Sterilisation A1.61, A1.66Storage Areas Ch. 3.19Storage, Blood and Plasma Products A14.17

Testing (Analysis)Active Pharmaceutical Ingredients PII.11.2Certificate, See Certificate of AnalysisContracting Ch. 6.6, Ch. 7.12Cross-contamination Ch. 5.19(g)Imported Products A16.6, A16.7In-Process Ch. 6.3Key Personnel Ch. 2.4(b), Ch. 2.6(iii)Methods, Validation Ch. 6.15, PII.12.8Multiple Batch Deliveries Ch. 5.28Procedures and Records Ch. 4.1, Ch. 4.23, Ch. 6.7, Ch. 6.17(c,e–g),

6.21, 6.22Quality Control Ch. 1.4, Ch. 6 (Principle), Ch. 6.15–6.22, A2.21Reprocessing Ch. 5.64Specifications Ch. 4.11(b,d), 6.17(c)Stability Testing Programme Ch. 6.27 to 6.29Sterility A1.91, A1.93Validation of Methods Ch. 6.15

Time Limits PII.8.2Toilet Facilities 3.31, PII.4.15Traceability

Active Pharmaceutical Ingredients PII.17.2Blood and Plasma Products A14.13–A14.14Dosimeter Calibration A12.5Investigational Medicinal Products A13.2, A13.6, A13.9, A13.47,

A13.55See also related topics: Audit Trail, Change Management, Document,

Management and Validation Records, inter-aliaTraders PII.17Training, Ch. 2 (Principle), Ch. 2.8–2.12, A8.1

Active Pharmaceutical Ingredients PII.3.12Biological Medicinal Products A2.1Hygiene Ch. 2.13Immunological Veterinary Products A5.1–A5.2Key Personnel Responsibilities Ch. 2.5(vi), 2.6(viii), Ch. 2.7


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Procedures and Records Ch. 4.26Radiopharmaceuticals A3.1Sterile Products A1.14

Transfer, Back-UpData and Electronic Records Ch. 4.9

Transfer OperationsContained/Clean Areas Ch. 3.6, A1.53, A5.48–A5.54Investigational Medicinal Products A13.47Isolators A1.7Liquids, Creams and Ointments A9.5–A9.6Medicinal Gases A6.5.2.10

Tuberculin Products A2.4, A2.8Two-shot Filling Process A10.1, A10.8Utilities PII.4.2

Product Quality Review Ch. 1.5(xi)Qualification Status Ch. 1.5(xi)

Vaccinations A2.3, A5.3Vaccines A1.41, A2.12, A2.21

Avoidance of Cross-contamination/Segregated Production AreasCh. 5.19

Validation A15, Gls.Active Pharmaceutical Ingredients PII.12, PII.19.6Analytical Methods Ch. 6.15, PII.12.8Campaign Working Ch. 3.6Cell bank system GlsCleaning A15.36–A15.42, PII.12.7, Gls.Computerised Systems A11.1–A11.2, A11.5, A11.7, A11.9, A11.11,

A11.16Concurrent A15.28–A15.30, Gls.Documentation A15.6–A15.8, PII.12.2Investigational Medicinal Products A13 (Principle), A13.17–A13.18,

A13.34, A13.40Ionising Radiation A12.4–A12.5, A12.9, A12.11(b), A12.29, A12.45Isolators A1.8Key Personnel Responsibilities Ch. 2.5, Ch. 2.6(vii), Ch. 2.7, A16.8.1(c)Laboratory Test Methods Ch. 6.7, Ch. 6.15, A19.7.1Medicinal Products Derived from Human Blood or Plasma

Donation and pool tests A14.16, A14.18–A14.19Storage and distribution temperatures A14.17Virus inactivation and removal A14 (principle), A14.24

Parametric Release, Sterile Products A17.3Periodic Review PII.12.6Planning A15.2–A15.5Policy PII.12.1


Procedures and Records Ch. 4.26, Ch. 4.28, Ch. 6.7Process A15.20–A15.35, PII.12.4–PII.12.5, Gls.Production Processes Ch. 5.21–5.24, Ch. 5.37, A1.42–A1.43, A1.54,

A2.38, A5.59Prospective A15.24–A15.27, Gls.Protocol Gls.Qualification A15.9–A15.19Qualified Person, Batch Release Certification A16.8.1(c)Quality Assurance Ch. 1.2(v)Radiation Treatment A12.9–A12.11Repeat, See Re-validationRetrospective A15.31–A15.35, Gls.Re-validation Ch. 1.5(xii), Ch. 5.24Sampling Starting Materials A8.2–A8.3Sterilisation A1.55–A1.58, A1.73, A1.76, A1.85Technical Agreements / Product Quality Review Ch. 1.5(xii)

Valves Gls.Cleaning A2.17, A5.25Metering, for Aerosols A10.4, A10.6Minimum Pressure Retention Gls.Non-Return Gls.

VentilationPremises Ch. 3.3Production Areas Ch. 3.10See Air Supply Systems

Veterinary Products A4Ectoparasiticides A4.5–A4.6Immunological, See Immunological Veterinary ProductsPenicillin Containing A4.7Premixes for Medicated Feedingstuffs A4.1–A4.4Retention of Samples A4.8–A4.9Sterile A4.10

Vials, Capping A5.62Viruses

Contaminating Blood and Plasma Products A14.15Removal/Inactivation A13.17, A14.23–A14.24, PII.18.5Safety, Cell Culture/Fermentation PII.18.1Testing for, Blood and Plasma Products A14.16, A14.18–A14.20See also Infectious Diseases

Visitors Ch. 2.11, A2.3Warehousing Procedures PII.10Warning Systems, Air Flow Failure A1.31Washing

Personnel Ch. 2.19


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Facilities Ch. 3.31, A1.27, PII.4.15Waste Disposal A2.19, A5.11, A5.32, A5.52, PII.4.6Water

Medicinal GasesCylinder contamination A6.5.3.6, A6.6.4Hydrostatic pressure test A6.6.1

Monitoring A1.44, A6.5.2.9, PII.4.34Quality A1.35, A6.5.2.9, A9.4, PII.4.3Sanitising Pipes Ch. 3.43Treatment A1.35, A1.44, A9.4, PII.4.33Utility Qualification Ch. 1.5(xi)

WeighingAvoidance of Cross-contamination Ch. 3.14Calibration Ch. 3.41Controls PII.8.12Processing Records Ch. 4.17(d)Rooms, Starting Materials Ch. 3.13

Workshops, Maintenance Ch. 3.32Worst Case Gls.Wristwatches A1.18Yield

Checks on Ch. 5.8, A5.64, A13.25, PII.8.14Deviations Ch. 5.39Expected Gls.Manufacturing Processes Ch. 4.14(d), Ch. 4.17(h), Ch. 5.8Quality Control Records Ch. 6.9Theoretical Gls.Validation Ch. 5.22

CHAPTER

2

EU Guidance on GoodManufacturing Practice

PART I: Basic Requirements for Medicinal Products

Editor’snote

The Introduction (below) to the EU Guidance on GMP which was written bythe Commission makes reference to a “glossary” of some terms used in theGuide for GMP. This glossary appears immediately after the annexes.

In addition to this glossary a number of the annexes themselves alsocontain a glossary of some of the terms used in the particular annex to whichthey are attached. This includes Annex 18, which is now covered under Part IIof the EU Guidance on GMP.

In this publication the Introduction (below) to the EU Guidance onGMP, the annexes including Annex 18 as described above and the glossaryreferred to in the Introduction have been presented as the Commissionintended.

Contents of Part I

1 Quality Management 43

Principle 43Quality Assurance 43Good Manufacturing Practice for

Medicinal Products (GMP) 44Quality Control 45Product Quality Review 46

2 Personnel 48

Principle 48General 48Key Personnel 48Training 50Personnel Hygiene 51

3 Premises and Equipment 53

Principle 53Premises 53General 53Production Area 53Storage Areas 55Quality Control Areas 55Ancillary Areas 56Equipment 56

4 Documentation 58

Principle 58General 58Documents Required 59

Contents continue

38


I II I

Specifications 59Specifications for Starting and

Packaging Materials 59Specifications for Intermediate and

Bulk Products 60Specifications for Finished

Products 60Manufacturing Formula and

Processing Instructions 60Packaging Instructions 61Batch Processing Records 62Batch Packaging Records 62Procedures and Records 63Receipt 63Sampling 64Testing 64Other 64

5 Production 66

Principle 66General 66Prevention of Cross-contamination in

Production 67Validation 68Starting Materials 68Processing Operations: intermediate

and bulk products 70Packaging Materials 70Packaging Operations 70Finished Products 72Rejected, Recovered and Returned

Materials 72

6 Quality Control 74

Principle 74General 74Good Quality Control Laboratory

Practice 75Documentation 75Sampling 76Testing 76On-going Stability Programme 77

7 Contract Manufactureand Analysis 80

Principle 80General 80The Contract Giver 80The Contract Acceptor 81The Contract 81

8 Complaints and ProductRecall 83

Principle 83Complaints 83Recalls 84

9 Self Inspection 85

Principle 85

Annex 1 Manufacture of SterileMedicinal Products 86

Annex 2 Manufacture of BiologicalMedicinal Products for HumanUse 103

Annex 3 Manufacture ofRadiopharmaceuticals 110

Annex 4 Manufacture of VeterinaryMedicinal Products Other ThanImmunological Veterinary MedicinalProducts 112

Annex 5 Manufacture ofImmunological VeterinaryMedicinal Products 115

Annex 6 Manufacture of MedicinalGases 127

Contents continue


Annex 7 Manufacture of HerbalMedicinal Products 137

Annex 8 Sampling of Starting andPackaging Materials 140

Annex 9 Manufacture of Liquids,Creams and Ointments 142

Annex 10 Manufacture ofPressurised Metered Dose AerosolPreparations for Inhalation 144

Annex 11 ComputerisedSystems 146

Annex 12 Use of IonisingRadiation in the Manufacture ofMedicinal Products 149

Annex 13 Manufacture ofInvestigational MedicinalProducts 156

Annex 14 Manufacture of MedicinalProducts Derived From HumanBlood or Plasma 172

Annex 15 Qualification andValidation 179

Annex 16 Certification by a QualifiedPerson and Batch Release 187

Annex 17 Parametric Release 197

Annex 18 Good ManufacturingPractice for Active PharmaceuticalIngredients 200

Annex 19 Reference and RetentionSamples 201

Glossary of Terms Used in the EUGuide to GMP 207

Introduction

The pharmaceutical industry of the European Union maintains high stan-dards of quality assurance in the development, manufacture and controlof medicinal products. A system of marketing authorisations ensures thatall medicinal products are assessed by a competent authority to ensurecompliance with contemporary requirements of safety, quality and effi-cacy. A system of manufacturing authorisations ensures that all productsauthorised on the European market are manufactured only by authorisedmanufacturers, whose activities are regularly inspected by the competentauthorities. Manufacturing authorisations are required by all pharmaceu-tical manufacturers in the European Community whether the products aresold within or outside of the Community.


I II I

Two directives laying down principles and guidelines of good manufac-turing practice (GMP) for medicinal products were adopted by the Com-mission. Directive 2003/94/EC applies to medicinal products for humanuse and Directive 91/412/EEC for veterinary use. Detailed guidelines inaccordance with those principles are published in the Guide to GoodManufacturing Practice, which will be used in assessing applications formanufacturing authorisations and as a basis for inspection of manufac-turers of medicinal products.

The principles of GMP and the detailed guidelines are applicable toall operations which require the authorisation referred to in Article 40of Directive 2001/83/EC and in Article 44 of Directive 2001/82/EC, asamended by Directives 2004/27/EC and 2004/28/EC, respectively. Theyare also relevant for all other large scale pharmaceutical manufacturingprocesses, such as that undertaken in hospitals, and for the preparation ofproducts for use in clinical trials.

All Member States and the industry agreed that the GMP requirementsapplicable to the manufacture of veterinary medicinal products are thesame as those applicable to the manufacture of medicinal products forhuman use. Certain detailed adjustments to the GMP guidelines are set outin two annexes specific to veterinary medicinal products and to immuno-logical veterinary medicinal products.

The Guide is presented in two parts of basic requirements and spe-cific annexes. Part I covers GMP principles for the manufacture of medi-cinal products. Part II covers GMP for active substances used as startingmaterials.

Chapters of Part I on “basic requirements” are headed by principles asdefined in Directives 2003/94/EC and 91/412/EEC. Chapter 1 on Qual-ity Management outlines the fundamental concept of quality assurance asapplied to the manufacture of medicinal products. Thereafter, each chapterhas a principle outlining the quality assurance objectives of that chapterand a text which provides sufficient detail for manufacturers to be madeaware of the essential matters to be considered when implementing theprinciple.

Part II was newly established on the basis of a guideline developed on thelevel of ICH and published as ICH Q7a on “active pharmaceutical ingredi-ents”, which was implemented as GMP Annex 18 for voluntary applicationin 2001. According to the revised Article 47 and Article 51, respectively, ofthe Directive 2001/83/EC and Directive 2001/82/EC, as amended, detailedguidelines on the principles of GMP for active substances used as startingmaterials shall be adopted and published by the Commission. The formerAnnex 18 has been replaced by the new Part II of the GMP Guide, whichhas an extended application both for the human and the veterinary sector.

In addition to the general matters of Good Manufacturing Practice out-lined in Parts I and II, a series of annexes providing detail about specific


areas of activity is included. For some manufacturing processes, differentannexes will apply simultaneously (e.g. annex on sterile preparations andon radiopharmaceuticals and/or on biological medicinal products).

A glossary of some terms used in the Guide has been incorporated afterthe annexes.

The Guide is not intended to cover security aspects for the personnelengaged in manufacture. This may be particularly important in the manu-facture of certain medicinal products such as highly active, biological andradioactive medicinal products. However, those aspects are governed byother provisions of Community or national law.

Throughout the Guide it is assumed that the requirements of theMarketing Authorisation relating to the safety, quality and efficacy of theproducts are systematically incorporated into all the manufacturing, con-trol and release for sale arrangements of the holder of the ManufacturingAuthorisation.

The manufacture of medicinal products has for many years taken placein accordance with guidelines for Good Manufacturing Practice and themanufacture of medicinal products is not governed by CEN/ISO stan-dards. Harmonised standards as adopted by the European standardisationorganisations CEN/ISO may be used at industry’s discretion as a tool forimplementing a quality system in the pharmaceutical sector. The CEN/ISOstandards have been considered but the terminology of these standards hasnot been implemented in this third edition of the Guide.

It is recognised that there are acceptable methods, other than thosedescribed in the Guide, which are capable of achieving the principles ofQuality Assurance. The Guide is not intended to place any restraint uponthe development of any new concepts or new technologies which have beenvalidated and which provide a level of Quality Assurance at least equivalentto those set out in this Guide. It will be regularly revised.


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1 QUALITY MANAGEMENT

Principle

The holder of a Manufacturing Authorisation must manufacture medicinalproducts so as to ensure that they are fit for their intended use, comply withthe requirements of the Marketing Authorisation and do not place patientsat risk due to inadequate safety, quality or efficacy. The attainment ofthis quality objective is the responsibility of senior management andrequires the participation and commitment by staff in many differentdepartments and at all levels within the company, by the company’s sup-pliers and by the distributors. To achieve the quality objective in a reliablemanner, there must be a comprehensively designed and correctly imple-mented system of Quality Assurance incorporating Good ManufacturingPractice and thus Quality Control. It should be fully documented and itseffectiveness monitored. All parts of the Quality Assurance system shouldbe adequately resourced with competent personnel, and suitable and suffi-cient premises, equipment and facilities. There are additional legal respon-sibilities for the holder of the Manufacturing Authorisation and for theQualified Person(s).

1.1 The basic concepts of Quality Assurance, Good Manufacturing Practiceand Quality Control are inter-related. They are described here in orderto emphasise their relationships and their fundamental importance to theproduction and control of medicinal products.

Quality Assurance

1.2 Quality Assurance is a wide ranging concept which covers all matters whichindividually or collectively influence the quality of a product. It is the totalsum of the organised arrangements made with the object of ensuring thatmedicinal products are of the quality required for their intended use. Qual-ity Assurance therefore incorporates Good Manufacturing Practice plusother factors outside the scope of this Guide. The system of Quality Assur-ance appropriate for the manufacture of medicinal products should ensurethat:

(i) medicinal products are designed and developed in a way that takesaccount of the requirements of Good Manufacturing Practice andGood Laboratory Practice;

(ii) production and control operations are clearly specified and GoodManufacturing Practice adopted;

(iii) managerial responsibilities are clearly specified;


(iv) arrangements are made for the manufacture, supply and use of thecorrect starting and packaging materials;

(v) all necessary controls on intermediate products, and any other in-process controls and validations are carried out;

(vi) the finished product is correctly processed and checked, according tothe defined procedures;

(vii) medicinal products are not sold or supplied before a Qualified Personhas certified that each production batch has been produced and con-trolled in accordance with the requirements of the Marketing Authori-sation and any other regulations relevant to the production, controland release of medicinal products;

(viii) satisfactory arrangements exist to ensure, as far as possible, that themedicinal products are stored, distributed and subsequently handledso that quality is maintained throughout their shelf life;

(ix) there is a procedure for Self-Inspection and/or quality audit whichregularly appraises the effectiveness and applicability of the QualityAssurance system.

Good Manufacturing Practice for Medicinal Products (GMP)

1.3 Good Manufacturing Practice is that part of Quality Assurance whichensures that products are consistently produced and controlled to the qual-ity standards appropriate to their intended use and as required by the Mar-keting Authorisation or product specification.

Good Manufacturing Practice is concerned with both production andquality control. The basic requirements of GMP are that:

(i) all manufacturing processes are clearly defined, systematicallyreviewed in the light of experience and shown to be capable of con-sistently manufacturing medicinal products of the required qualityand complying with their specifications;

(ii) critical steps of manufacturing processes and significant changes tothe process are validated;

(iii) all necessary facilities for GMP are provided including:(iv) appropriately qualified and trained personnel;(v) adequate premises and space;(vi) suitable equipment and services;(vii) correct materials, containers and labels;(viii) approved procedures and instructions;(ix) suitable storage and transport;(x) instructions and procedures are written in an instructional form in

clear and unambiguous language, specifically applicable to the facil-ities provided;


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(xi) operators are trained to carry out procedures correctly;(xii) records are made, manually and/or by recording instruments, during

manufacture which demonstrate that all the steps required by thedefined procedures and instructions were in fact taken and that thequantity and quality of the product was as expected. Any significantdeviations are fully recorded and investigated;

(xiii) records of manufacture including distribution which enable the com-plete history of a batch to be traced, are retained in a comprehensibleand accessible form;

(xiv) the distribution (wholesaling) of the products minimises any risk totheir quality;

(xv) a system is available to recall any batch of product, from sale orsupply;

(xvi) complaints about marketed products are examined, the causes ofquality defects investigated and appropriate measures taken in respectof the defective products and to prevent reoccurrence.

Quality Control

1.4 Quality Control is that part of Good Manufacturing Practice which is con-cerned with sampling, specifications and testing, and with the organisation,documentation and release procedures which ensure that the necessary andrelevant tests are actually carried out and that materials are not releasedfor use, nor products released for sale or supply, until their quality has beenjudged to be satisfactory. The basic requirements of Quality Control arethat:

(i) adequate facilities, trained personnel and approved procedures areavailable for sampling, inspecting and testing starting materials,packaging materials, intermediate, bulk, and finished products, andwhere appropriate for monitoring environmental conditions for GMPpurposes;

(ii) samples of starting materials, packaging materials, intermediateproducts, bulk products and finished products are taken by personneland by methods approved by Quality Control;

(iii) test methods are validated;(iv) records are made, manually and/or by recording instruments, which

demonstrate that all the required sampling, inspecting and test-ing procedures were actually carried out. Any deviations are fullyrecorded and investigated;

(v) the finished products contain active ingredients complying withthe qualitative and quantitative composition of the Marketing


Authorisation, are of the purity required, and are enclosed withintheir proper containers and correctly labelled;

(vi) records are made of the results of inspection and that testing of ma-terials, intermediate, bulk, and finished products is formally assessedagainst specification. Product assessment includes a review and eval-uation of relevant production documentation and an assessment ofdeviations from specified procedures;

(vii) no batch of product is released for sale or supply prior to certificationby a Qualified Person that it is in accordance with the requirementsof the Marketing Authorisation;

(viii) sufficient reference samples of starting materials and products areretained to permit future examination of the product if necessaryand that the product is retained in its final pack unless exceptionallylarge packs are produced.

Product Quality Review

1.5 Regular periodic or rolling quality reviews of all licensed medicinal prod-ucts, including export only products, should be conducted with the objec-tive of verifying the consistency of the existing process, the appropriatenessof current specifications for both starting materials and finished productto highlight any trends and to identify product and process improvements.Such reviews should normally be conducted and documented annually,taking into account previous reviews, and should include at least:

(i) A review of starting materials and packaging materials used for theproduct, especially those from new sources;

(ii) A review of critical in-process controls and finished product results;(iii) A review of all batches that failed to meet established specification(s)

and their investigation;(iv) A review of all significant deviations or non-conformances, their

related investigations, and the effectiveness of resultant correctiveand preventative actions taken;

(v) A review of all changes carried out to the processes or analyticalmethods;

(vi) A review of Marketing Authorisation variations submitted/granted/refused, including those for third country (export only) dossiers;

(vii) A review of the results of the stability monitoring programme andany adverse trends;

(viii) A review of all quality-related returns, complaints and recalls and theinvestigations performed at the time;

(ix) A review of adequacy of any other previous product process or equip-ment corrective actions;


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(x) For new marketing authorisations and variations to marketing autho-risations, a review of post-marketing commitments;

(xi) The qualification status of relevant equipment and utilities, e.g.HVAC, water, compressed gases, etc;

(xii) A review of Technical Agreements to ensure that they are up to date.

The manufacturer and marketing authorisation holder, where different,should evaluate the results of this review and an assessment should be madewhether corrective and preventative action or any revalidation should beundertaken. Reasons for such corrective actions should be documented.Agreed corrective and preventative actions should be completed in a timelyand effective manner. There should be management procedures for theongoing management and review of these actions and the effectiveness ofthese procedures verified during self inspection. Quality reviews may begrouped by product type, e.g. solid dosage forms, liquid dosage forms,sterile products, etc. where scientifically justified.

Where the marketing authorisation holder is not the manufacturer, thereshould be a technical agreement in place between the various parties thatdefines their respective responsibilities in producing the quality review. TheQualified Person responsible for final batch certification together with themarketing authorisation holder should ensure that the quality review isperformed in a timely manner and is accurate.


2 PERSONNEL

Principle

The establishment and maintenance of a satisfactory system of qualityassurance and the correct manufacture of medicinal products relies uponpeople. For this reason there must be sufficient qualified personnel to carryout all the tasks which are the responsibility of the manufacturer. Indi-vidual responsibilities should be clearly understood by the individuals andrecorded. All personnel should be aware of the principles of Good Manu-facturing Practice that affect them and receive initial and continuing train-ing, including hygiene instructions, relevant to their needs.

General

2.1 The manufacturer should have an adequate number of personnel withthe necessary qualifications and practical experience. The responsibilitiesplaced on any one individual should not be so extensive as to present anyrisk to quality.

2.2 The manufacturer must have an organisation chart. People in responsiblepositions should have specific duties recorded in written job descriptionsand adequate authority to carry out their responsibilities. Their duties maybe delegated to designated deputies of a satisfactory qualification level.There should be no gaps or unexplained overlaps in the responsibilities ofthose personnel concerned with the application of Good ManufacturingPractice.

Key Personnel

2.3 Key Personnel include the head of Production, the head of Quality Con-trol, and if at least one of these persons is not responsible for the dutiesdescribed in Article 51 of Directive 2001/83/EC,1 the Qualified Person(s)designated for the purpose. Normally key posts should be occupied byfull-time personnel. The heads of Production and Quality Control must beindependent from each other. In large organisations, it may be necessaryto delegate some of the functions listed in 2.5, 2.6 and 2.7.

2.4 The duties of the Qualified Person(s) are fully described in Article 51 ofDirective 2001/83/EC, and can be summarised as follows:

1 Article 55 of Directive 2001/82/EC.


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(a) for medicinal products manufactured within the European Community,a Qualified Person must ensure that each batch has been producedand tested/checked in accordance with the directives and the marketingauthorisation;2

(b) for medicinal products manufactured outside the European Commu-nity, a Qualified Person must ensure that each imported batch hasundergone, in the importing country, the testing specified in paragraph1 (b) of Article 51;

(c) a Qualified Person must certify in a register or equivalent document, asoperations are carried out and before any release, that each productionbatch satisfies the provisions of Article 51.

The persons responsible for these duties must meet the qualificationrequirements laid down in Article 493 of the same Directive, they shall bepermanently and continuously at the disposal of the holder of the Manu-facturing Authorisation to carry out their responsibilities. Their responsi-bilities may be delegated, but only to other Qualified Person(s).

2.5 The head of the Production Department generally has the following respon-sibilities:

(i) to ensure that products are produced and stored according to theappropriate documentation in order to obtain the required quality;

(ii) to approve the instructions relating to production operations and toensure their strict implementation;

(iii) to ensure that the production records are evaluated and signed by anauthorised person before they are sent to the Quality Control Depart-ment;

(iv) to check the maintenance of his department, premises and equipment;(v) to ensure that the appropriate validations are done;(vi) to ensure that the required initial and continuing training of his depart-

ment personnel is carried out and adapted according to need.

2.6 The head of the Quality Control Department generally has the followingresponsibilities:

(i) to approve or reject, as he sees fit, starting materials, packaging ma-terials, and intermediate, bulk and finished products;

(ii) to evaluate batch records;

2 According to Directive 75/319/EEC (now codified Directive 2001/83/EC) and theruling of the Court of Justice of the European Communities, medicinal productswhich have been properly controlled in the EU by a Qualified Person do not haveto be recontrolled or rechecked in any other Member State of the Community.

3 Article 53 of Directive 2001/82/EC.


(iii) to ensure that all necessary testing is carried out;(iv) to approve specifications, sampling instructions, test methods and

other Quality Control procedures;(v) to approve and monitor any contract analysts;(vi) to check the maintenance of his department, premises and equipment;(vii) to ensure that the appropriate validations are done;(viii) to ensure that the required initial and continuing training of his

department personnel is carried out and adapted according toneed.

Other duties of the Quality Control Department are summarised inChapter 6.

2.7 The heads of Production and Quality Control generally have some shared,or jointly exercised, responsibilities relating to quality. These may include,subject to any national regulations:

� the authorisation of written procedures and other documents, includingamendments;

� the monitoring and control of the manufacturing environment;� plant hygiene;� process validation;� training;� the approval and monitoring of suppliers of materials;� the approval and monitoring of contract manufacturers;� the designation and monitoring of storage conditions for materials and

products;� the retention of records;� the monitoring of compliance with the requirements of Good Manufac-

turing Practice;� the inspection, investigation, and taking of samples, in order to monitor

factors which may affect product quality.

Training

2.8 The manufacturer should provide training for all the personnel whoseduties take them into production areas or into control laboratories (includ-ing the technical, maintenance and cleaning personnel), and for otherpersonnel whose activities could affect the quality of the product.

2.9 Besides the basic training on the theory and practice of Good Manufactur-ing Practice, newly recruited personnel should receive training appropriateto the duties assigned to them. Continuing training should also be given,and its practical effectiveness should be periodically assessed. Training pro-grammes should be available, approved by either the head of Production


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or the head of Quality Control, as appropriate. Training records should bekept.

2.10 Personnel working in areas where contamination is a hazard, e.g. cleanareas or areas where highly active, toxic, infectious or sensitising materialsare handled, should be given specific training.

2.11 Visitors or untrained personnel should, preferably, not be taken intothe Production and Quality Control areas. If this is unavoidable, theyshould be given information in advance, particularly about personalhygiene and the prescribed protective clothing. They should be closelysupervised.

2.12 The concept of Quality Assurance and all the measures capable of improv-ing its understanding and implementation should be fully discussed duringthe training sessions.

Personnel Hygiene

2.13 Detailed hygiene programmes should be established and adapted to thedifferent needs within the factory. They should include procedures relatingto the health, hygiene practices and clothing of personnel. These proceduresshould be understood and followed in a very strict way by every personwhose duties take him into the production and control areas. Hygieneprogrammes should be promoted by management and widely discussedduring training sessions.

2.14 All personnel should receive medical examination upon recruitment. Itmust be the manufacturer’s responsibility that there are instructions ensur-ing that health conditions that can be of relevance to the quality of productscome to the manufacturer’s knowledge. After the first medical examina-tion, examinations should be carried out when necessary for the work andpersonal health.

2.15 Steps should be taken to ensure as far as is practicable that no personaffected by an infectious disease or having open lesions on the exposedsurface of the body is engaged in the manufacture of medicinal products.

2.16 Every person entering the manufacturing areas should wear protective gar-ments appropriate to the operations to be carried out.

2.17 Eating, drinking, chewing or smoking, or the storage of food, drink, smok-ing materials or personal medication in the production and storage areasshould be prohibited. In general, any unhygienic practice within the manu-facturing areas or in any other area where the product might be adverselyaffected, should be forbidden.


2.18 Direct contact should be avoided between the operator’s hands and theexposed product as well as with any part of the equipment that comes intocontact with the products.

2.19 Personnel should be instructed to use the hand-washing facilities.

2.20 Any specific requirements for the manufacture of special groups of prod-ucts, for example sterile preparations, are covered in the annexes.


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3 PREMISES AND EQUIPMENT

Principle

Premises and equipment must be located, designed, constructed, adaptedand maintained to suit the operations to be carried out. Their layoutand design must aim to minimise the risk of errors and permit effectivecleaning and maintenance in order to avoid cross-contamination, buildup of dust or dirt and, in general, any adverse effect on the quality ofproducts.

Premises

General

3.1 Premises should be situated in an environment which, when consideredtogether with measures to protect the manufacture, presents minimal riskof causing contamination of materials or products.

3.2 Premises should be carefully maintained, ensuring that repair and main-tenance operations do not present any hazard to the quality of products.They should be cleaned and, where applicable, disinfected according todetailed written procedures.

3.3 Lighting, temperature, humidity and ventilation should be appropriate andsuch that they do not adversely affect, directly or indirectly, either themedicinal products during their manufacture and storage, or the accuratefunctioning of equipment.

3.4 Premises should be designed and equipped so as to afford maximum pro-tection against the entry of insects or other animals.

3.5 Steps should be taken in order to prevent the entry of unauthorised people.Production, storage and quality control areas should not be used as a rightof way by personnel who do not work in them.

Production Area

3.6 In order to minimise the risk of a serious medical hazard due to cross-contamination, dedicated and self contained facilities must be availablefor the production of particular medicinal products, such as highly sen-sitising materials (e.g. penicillins) or biological preparations (e.g. fromlive micro-organisms). The production of certain additional products, suchas certain antibiotics, certain hormones, certain cytotoxics, certain highlyactive drugs and non-medicinal products should not be conducted in the


same facilities. For those products, in exceptional cases, the principle ofcampaign working in the same facilities can be accepted provided thatspecific precautions are taken and the necessary validations are made.The manufacture of technical poisons, such as pesticides and herbicides,should not be allowed in premises used for the manufacture of medicinalproducts.

3.7 Premises should preferably be laid out in such a way as to allow the pro-duction to take place in areas connected in a logical order correspond-ing to the sequence of the operations and to the requisite cleanlinesslevels.

3.8 The adequacy of the working and in-process storage space should permitthe orderly and logical positioning of equipment and materials so as tominimise the risk of confusion between different medicinal products ortheir components, to avoid cross-contamination and to minimise the riskof omission or wrong application of any of the manufacturing or controlsteps.

3.9 Where starting and primary packaging materials, intermediate or bulkproducts are exposed to the environment, interior surfaces (walls, floorsand ceilings) should be smooth, free from cracks and open joints, andshould not shed particulate matter and should permit easy and effectivecleaning and, if necessary, disinfection.

3.10 Pipework, light fittings, ventilation points and other services should bedesigned and sited to avoid the creation of recesses which are difficultto clean. As far as possible, for maintenance purposes, they should beaccessible from outside the manufacturing areas.

3.11 Drains should be of adequate size, and have trapped gullies. Open channelsshould be avoided where possible, but if necessary, they should be shallowto facilitate cleaning and disinfection.

3.12 Production areas should be effectively ventilated, with air control facili-ties (including temperature and, where necessary, humidity and filtration)appropriate both to the products handled, to the operations undertakenwithin them and to the external environment.

3.13 Weighing of starting materials usually should be carried out in a separateweighing room designed for that use.

3.14 In cases where dust is generated (e.g. during sampling, weighing, mixingand processing operations, packaging of dry products), specific provisionsshould be taken to avoid cross-contamination and facilitate cleaning.

3.15 Premises for the packaging of medicinal products should be specificallydesigned and laid out so as to avoid mix-ups or cross-contamination.


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3.16 Production areas should be well lit, particularly where visual on-line con-trols are carried out.

3.17 In-process controls may be carried out within the production area providedthey do not carry any risk for the production.

Storage Areas

3.18 Storage areas should be of sufficient capacity to allow orderly storage ofthe various categories of materials and products: starting and packagingmaterials, intermediate, bulk and finished products, products in quaran-tine, released, rejected, returned or recalled.

3.19 Storage areas should be designed or adapted to ensure good storageconditions. In particular, they should be clean and dry and maintainedwithin acceptable temperature limits. Where special storage conditions arerequired (e.g. temperature, humidity) these should be provided, checkedand monitored.

3.20 Receiving and dispatch bays should protect materials and products fromthe weather. Reception areas should be designed and equipped to allowcontainers of incoming materials to be cleaned where necessary beforestorage.

3.21 Where quarantine status is ensured by storage in separate areas, these areasmust be clearly marked and their access restricted to authorised person-nel. Any system replacing the physical quarantine should give equivalentsecurity.

3.22 There should normally be a separate sampling area for starting materials.If sampling is performed in the storage area, it should be conducted in sucha way as to prevent contamination or cross-contamination.

3.23 Segregated areas should be provided for the storage of rejected, recalled orreturned materials or products.

3.24 Highly active materials or products should be stored in safe and secureareas.

3.25 Printed packaging materials are considered critical to the conformity ofthe medicinal product and special attention should be paid to the safe andsecure storage of these materials.

Quality Control Areas

3.26 Normally, Quality Control laboratories should be separated from produc-tion areas. This is particularly important for laboratories for the control


of biologicals, microbiologicals and radioisotopes, which should also beseparated from each other.

3.27 Control laboratories should be designed to suit the operations to be car-ried out in them. Sufficient space should be given to avoid mix-ups andcross-contamination. There should be adequate suitable storage space forsamples and records.

3.28 Separate rooms may be necessary to protect sensitive instruments fromvibration, electrical interference, humidity, etc.

3.29 Special requirements are needed in laboratories handling particular sub-stances, such as biological or radioactive samples.

Ancillary Areas

3.30 Rest and refreshment rooms should be separate from other areas.

3.31 Facilities for changing clothes, and for washing and toilet purposesshould be easily accessible and appropriate for the number of users.Toilets should not directly communicate with production or storageareas.

3.32 Maintenance workshops should as far as possible be separated from pro-duction areas. Whenever parts and tools are stored in the production area,they should be kept in rooms or lockers reserved for that use.

3.33 Animal houses should be well isolated from other areas, with separateentrance (animal access) and air handling facilities.

Equipment

3.34 Manufacturing equipment should be designed, located and maintained tosuit its intended purpose.

3.35 Repair and maintenance operations should not present any hazard to thequality of the products.

3.36 Manufacturing equipment should be designed so that it can be easily andthoroughly cleaned. It should be cleaned according to detailed and writtenprocedures and stored only in a clean and dry condition.

3.37 Washing and cleaning equipment should be chosen and used in order notto be a source of contamination.

3.38 Equipment should be installed in such a way as to prevent any risk of erroror of contamination.


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3.39 Production equipment should not present any hazard to the products. Theparts of the production equipment that come into contact with the productmust not be reactive, additive or absorptive to such an extent that it willaffect the quality of the product and thus present any hazard.

3.40 Balances and measuring equipment of an appropriate range and precisionshould be available for production and control operations.

3.41 Measuring, weighing, recording and control equipment should be cali-brated and checked at defined intervals by appropriate methods. Adequaterecords of such tests should be maintained.

3.42 Fixed pipework should be clearly labelled to indicate the contents and,where applicable, the direction of flow.

3.43 Distilled, deionized and, where appropriate, other water pipes should besanitised according to written procedures that detail the action limits formicrobiological contamination and the measures to be taken.

3.44 Defective equipment should, if possible, be removed from production andquality control areas, or at least be clearly labelled as defective.


4 DOCUMENTATION

Principle

Good documentation constitutes an essential part of the quality assur-ance system. Clearly written documentation prevents errors from spo-ken communication and permits tracing of batch history. Specifications,Manufacturing Formulae and instructions, procedures, and records mustbe free from errors and available in writing. The legibility of documents isof paramount importance.

General

4.1 Specifications describe in detail the requirements with which the productsor materials used or obtained during manufacture have to conform. Theyserve as a basis for quality evaluation.

Manufacturing Formulae, Processing and Packaging Instructions stateall the starting materials used and lay down all processing and packagingoperations.

Procedures give directions for performing certain operations e.g. clean-ing, clothing, environmental control, sampling, testing, equipment opera-tion.

Records provide a history of each batch of product, including its distri-bution, and also of all other relevant circumstances pertinent to the qualityof the final product.

4.2 Documents should be designed, prepared, reviewed and distributed withcare. They should comply with the relevant parts of the manufacturing andmarketing authorisation dossiers.

4.3 Documents should be approved, signed and dated by appropriate andauthorised persons.

4.4 Documents should have unambiguous contents; title, nature and purposeshould be clearly stated. They should be laid out in an orderly fashionand be easy to check. Reproduced documents should be clear and leg-ible. The reproduction of working documents from master documentsmust not allow any error to be introduced through the reproductionprocess.

4.5 Documents should be regularly reviewed and kept up-to-date. When a doc-ument has been revised, systems should be operated to prevent inadvertentuse of superseded documents.


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4.6 Documents should not be handwritten; although, where documents requirethe entry of data, these entries may be made in clear, legible, indeliblehandwriting. Sufficient space should be provided for such entries.

4.7 Any alteration made to the entry on a document should be signed anddated; the alteration should permit the reading of the original information.Where appropriate, the reason for the alteration should be recorded.

4.8 The records should be made or completed at the time each action is takenand in such a way that all significant activities concerning the manufactureof medicinal products are traceable. They should be retained for at leastone year after the expiry date of the finished product.

4.9 Data may be recorded by electronic data processing systems, photographicor other reliable means, but detailed procedures relating to the system inuse should be available and the accuracy of the records should be checked.If documentation is handled by electronic data processing methods, onlyauthorised persons should be able to enter or modify data in the computerand there should be a record of changes and deletions; access should berestricted by passwords or other means and the result of entry of criticaldata should be independently checked. Batch records electronically storedshould be protected by back-up transfer on magnetic tape, microfilm, paperor other means. It is particularly important that the data are readily avail-able throughout the period of retention.

Documents Required

Specifications

4.10 There should be appropriately authorised and dated specifications for start-ing and packaging materials, and finished products; where appropriate,they should be also available for intermediate or bulk products.

Specifications for Starting and Packaging Materials

4.11 Specifications for starting and primary or printed packaging materialsshould include, if applicable:

(a) a description of the materials, including:� the designated name and the internal code reference,� the reference, if any, to a pharmacopoeial monograph,� the approved suppliers and, if possible, the original producer of the

products,� a specimen of printed materials;


(b) directions for sampling and testing or reference to procedures;(c) qualitative and quantitative requirements with acceptance limits;(d) storage conditions and precautions;(e) the maximum period of storage before re-examination.

Specifications for Intermediate and Bulk Products

4.12 Specifications for intermediate and bulk products should be available ifthese are purchased or dispatched, or if data obtained from intermedi-ate products are used for the evaluation of the finished product. Thespecifications should be similar to specifications for starting materials orfor finished products, as appropriate.

Specifications for Finished Products

4.13 Specifications for finished products should include:

(a) the designated name of the product and the code reference where appli-cable;

(b) the formula or a reference to;(c) a description of the pharmaceutical form and package details;(d) directions for sampling and testing or a reference to procedures;(e) the qualitative and quantitative requirements, with the acceptance

limits;(f) the storage conditions and any special handling precautions, where

applicable;(g) the shelf-life.

Manufacturing Formula and Processing Instructions

Formally authorised Manufacturing Formula and Processing Instructionsshould exist for each product and batch size to be manufactured. They areoften combined in one document.

4.14 The Manufacturing Formula should include:

(a) the name of the product, with a product reference code relating to itsspecification;

(b) a description of the pharmaceutical form, strength of the product andbatch size;

(c) a list of all starting materials to be used, with the amount of each,described using the designated name and a reference which is unique


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to that material; mention should be made of any substance that maydisappear in the course of processing;

(d) a statement of the expected final yield with the acceptable limits, andof relevant intermediate yields, where applicable.

4.15 The Processing Instructions should include:

(a) a statement of the processing location and the principal equipment tobe used;

(b) the methods, or reference to the methods, to be used for preparing thecritical equipment (e.g. cleaning, assembling, calibrating, sterilising);

(c) detailed stepwise processing instructions (e.g. checks on materials, pre-treatments, sequence for adding materials, mixing times, temperatures);

(d) the instructions for any in-process controls with their limits;(e) where necessary, the requirements for bulk storage of the products;

including the container, labelling and special storage conditions whereapplicable;

(f) any special precautions to be observed.

Packaging Instructions

4.16 There should be formally authorised Packaging Instructions for each prod-uct, pack size and type. These should normally include, or have a referenceto, the following:

(a) name of the product;(b) description of its pharmaceutical form, and strength where applicable;(c) the pack size expressed in terms of the number, weight or volume of the

product in the final container;(d) a complete list of all the packaging materials required for a stan-

dard batch size, including quantities, sizes and types, with the codeor reference number relating to the specifications of each packagingmaterial;

(e) where appropriate, an example or reproduction of the relevant printedpackaging materials, and specimens indicating where to apply batchnumber references, and shelf life of the product;

(f) special precautions to be observed, including a careful examination ofthe area and equipment in order to ascertain the line clearance beforeoperations begin;

(g) a description of the packaging operation, including any significantsubsidiary operations, and equipment to be used;

(h) details of in-process controls with instructions for sampling and accep-tance limits.


Batch Processing Records

4.17 A Batch Processing Record should be kept for each batch processed. Itshould be based on the relevant parts of the currently approved Manufac-turing Formula and Processing Instructions. The method of preparation ofsuch records should be designed to avoid transcription errors. The recordshould carry the number of the batch being manufactured.

Before any processing begins, there should be recorded checks that theequipment and work station are clear of previous products, documents ormaterials not required for the planned process, and that equipment is cleanand suitable for use.

During processing, the following information should be recorded at thetime each action is taken and, after completion, the record should bedated and signed in agreement by the person responsible for the processingoperations:

(a) the name of the product;(b) dates and times of commencement, of significant intermediate stages

and of completion of production;(c) name of the person responsible for each stage of production;(d) initials of the operator of different significant steps of production and,

where appropriate, of the person who checked each of these operations(e.g. weighing);

(e) the batch number and/or analytical control number as well as the quan-tities of each starting material actually weighed (including the batchnumber and amount of any recovered or reprocessed material added);

(f) any relevant processing operation or event and major equipment used;(g) a record of the in-process controls and the initials of the person(s)

carrying them out, and the results obtained;(h) the product yield obtained at different and pertinent stages of manu-

facture;(i) notes on special problems including details, with signed authorisation

for any deviation from the Manufacturing Formula and ProcessingInstructions.

Batch Packaging Records

4.18 A Batch Packaging Record should be kept for each batch or part batch pro-cessed. It should be based on the relevant parts of the Packaging Instruc-tions and the method of preparation of such records should be designed toavoid transcription errors. The record should carry the batch number andthe quantity of bulk product to be packed, as well as the batch numberand the planned quantity of finished product that will be obtained.


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Before any packaging operation begins, there should be recorded checksthat the equipment and work station are clear of previous products, docu-ments or materials not required for the planned packaging operations, andthat equipment is clean and suitable for use.

The following information should be entered at the time each actionis taken and, after completion, the record should be dated and signed inagreement by the person(s) responsible for the packaging operations:

(a) the name of the product;(b) the date(s) and times of the packaging operations;(c) the name of the responsible person carrying out the packaging opera-

tion;(d) the initials of the operators of the different significant steps;(e) records of checks for identity and conformity with the packaging

instructions including the results of in-process controls;(f) details of the packaging operations carried out, including references to

equipment and the packaging lines used;(g) whenever possible, samples of printed packaging materials used, includ-

ing specimens of the batch coding, expiry dating and any additionaloverprinting;

(h) notes on any special problems or unusual events including details, withsigned authorisation for any deviation from the Manufacturing For-mula and Processing Instructions;

(i) the quantities and reference number or identification of all printed pack-aging materials and bulk product issued, used, destroyed or returnedto stock and the quantities of obtained product, in order to provide foran adequate reconciliation.

Procedures and Records

Receipt

4.19 There should be written procedures and records for the receipt of eachdelivery of each starting and primary and printed packaging material.

4.20 The records of the receipts should include:

(a) the name of the material on the delivery note and the containers;(b) the “in-house” name and/or code of material (if different from a);(c) date of receipt;(d) supplier’s name and, if possible, manufacturer’s name;(e) manufacturer’s batch or reference number(f) total quantity, and number of containers received;(g) the batch number assigned after receipt;(h) any relevant comment (e.g. state of the containers).


4.21 There should be written procedures for the internal labelling, quarantineand storage of starting materials, packaging materials and other materials,as appropriate.

Sampling

4.22 There should be written procedures for sampling, which include the per-son(s) authorised to take samples, the methods and equipment to be used,the amounts to be taken and any precautions to be observed to avoid con-tamination of the material or any deterioration in its quality (see Section II,Chapter 6, item 13).

Testing

4.23 There should be written procedures for testing materials and products atdifferent stages of manufacture, describing the methods and equipment tobe used. The tests performed should be recorded (see Section II, Chapter 6,item 17).

Other

4.24 Written release and rejection procedures should be available for materi-als and products, and in particular for the release for sale of the finishedproduct by the Qualified Person(s) in accordance with the requirements ofArticle 51 of Directive 2001/83/EC.1

4.25 Records should be maintained of the distribution of each batch of a productin order to facilitate the recall of the batch if necessary (see Section II,Chapter 8).

4.26 There should be written procedures and the associated records of actionstaken or conclusions reached, where appropriate, for:

� validation;� equipment assembly and calibration;� maintenance, cleaning and sanitation;� personnel matters including training, clothing, hygiene;� environmental monitoring;� pest control;� complaints;� recalls;� returns.

1 Article 55 of the Directive 2001/82/EC.


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4.27 Clear operating procedures should be available for major items of manu-facturing and test equipment.

4.28 Log books should be kept for major or critical equipment recording, asappropriate, any validations, calibrations, maintenance, cleaning or repairoperations, including the dates and identity of people who carried theseoperations out.

4.29 Log books should also record in chronological order the use of major orcritical equipment and the areas where the products have been processed.


5 PRODUCTION

Principle

Production operations must follow clearly defined procedures; they mustcomply with the principles of Good Manufacturing Practice in order toobtain products of the requisite quality and be in accordance with therelevant manufacturing and marketing authorisations.

General

5.1 Production should be performed and supervised by competent people.

5.2 All handling of materials and products, such as receipt and quarantine,sampling, storage, labelling, dispensing, processing, packaging and distri-bution should be done in accordance with written procedures or instruc-tions and, where necessary, recorded.

5.3 All incoming materials should be checked to ensure that the consignmentcorresponds to the order. Containers should be cleaned where necessaryand labelled with the prescribed data.

5.4 Damage to containers and any other problems which might adversely affectthe quality of a material should be investigated, recorded and reported tothe Quality Control Department.

5.5 Incoming materials and finished products should be physically or admin-istratively quarantined immediately after receipt or processing, until theyhave been released for use or distribution.

5.6 Intermediate and bulk products purchased as such should be handled onreceipt as though they were starting materials.

5.7 All materials and products should be stored under the appropriate condi-tions established by the manufacturer and in an orderly fashion to permitbatch segregation and stock rotation.

5.8 Checks on yields, and reconciliation of quantities, should be carried outas necessary to ensure that there are no discrepancies outside acceptablelimits.

5.9 Operations on different products should not be carried out simultaneouslyor consecutively in the same room unless there is no risk of mix-up orcross-contamination.

5.10 At every stage of processing, products and materials should be protectedfrom microbial and other contamination.


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5.11 When working with dry materials and products, special precautions shouldbe taken to prevent the generation and dissemination of dust. This appliesparticularly to the handling of highly active or sensitising materials.

5.12 At all times during processing, all materials, bulk containers, major itemsof equipment and where appropriate rooms used should be labelledor otherwise identified with an indication of the product or mater-ial being processed, its strength (where applicable) and batch number.Where applicable, this indication should also mention the stage ofproduction.

5.13 Labels applied to containers, equipment or premises should be clear, un-ambiguous and in the company’s agreed format. It is often helpful in addi-tion to the wording on the labels to use colours to indicate status (forexample, quarantined, accepted, rejected, clean, . . . ).

5.14 Checks should be carried out to ensure that pipelines and other pieces ofequipment used for the transportation of products from one area to anotherare connected in a correct manner.

5.15 Any deviation from instructions or procedures should be avoided as far aspossible. If a deviation occurs, it should be approved in writing by a com-petent person, with the involvement of the Quality Control Departmentwhen appropriate.

5.16 Access to production premises should be restricted to authorisedpersonnel.

5.17 Normally, the production of non-medicinal products should be avoidedin areas and with the equipment destined for the production of medicinalproducts.

Prevention of Cross-contamination in Production

5.18 Contamination of a starting material or of a product by another material orproduct must be avoided. This risk of accidental cross-contamination arisesfrom the uncontrolled release of dust, gases, vapours, sprays or organismsfrom materials and products in process, from residues on equipment, andfrom operators’ clothing. The significance of this risk varies with the type ofcontaminant and of product being contaminated. Amongst the most haz-ardous contaminants are highly sensitising materials, biological prepara-tions containing living organisms, certain hormones, cytotoxics and otherhighly active materials. Products in which contamination is likely to bemost significant are those administered by injection, those given in largedoses and/or over a long time.


5.19 Cross-contamination should be avoided by appropriate technical or organ-isational measures, for example:

(a) production in segregated areas (required for products such as peni-cillins, live vaccines, live bacterial preparations and some other bio-logicals), or by campaign (separation in time) followed by appropriatecleaning;

(b) providing appropriate air-locks and air extraction;(c) minimising the risk of contamination caused by recirculation or re-entry

of untreated or insufficiently treated air;(d) keeping protective clothing inside areas where products with special

risk of cross-contamination are processed;(e) using cleaning and decontamination procedures of known effective-

ness, as ineffective cleaning of equipment is a common source of cross-contamination;

(f) using “closed systems” of production;(g) testing for residues and use of cleaning status labels on equipment.

5.20 Measures to prevent cross-contamination and their effectiveness should bechecked periodically according to set procedures.

Validation

5.21 Validation studies should reinforce Good Manufacturing Practice and beconducted in accordance with defined procedures. Results and conclusionsshould be recorded.

5.22 When any new manufacturing formula or method of preparation isadopted, steps should be taken to demonstrate its suitability for routineprocessing. The defined process, using the materials and equipment speci-fied, should be shown to yield a product consistently of the required quality.

5.23 Significant amendments to the manufacturing process, including anychange in equipment or materials, which may affect product quality and/orthe reproducibility of the process should be validated.

5.24 Processes and procedures should undergo periodic critical re-validation toensure that they remain capable of achieving the intended results.

Starting Materials

5.25 The purchase of starting materials is an important operation which shouldinvolve staff who have a particular and thorough knowledge of thesuppliers.


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5.26 Starting materials should only be purchased from approved suppliersnamed in the relevant specification and, where possible, directly fromthe producer. It is recommended that the specifications established by themanufacturer for the starting materials be discussed with the suppliers. Itis of benefit that all aspects of the production and control of the startingmaterial in question, including handling, labelling and packaging require-ments, as well as complaints and rejection procedures are discussed withthe manufacturer and the supplier.

5.27 For each delivery, the containers should be checked for integrity of pack-age and seal and for correspondence between the delivery note and thesupplier’s labels.

5.28 If one material delivery is made up of different batches, each batch mustbe considered as separate for sampling, testing and release.

5.29 Starting materials in the storage area should be appropriately labelled (seeSection II, Chapter 5, item 13). Labels should bear at least the followinginformation:

� the designated name of the product and the internal code reference whereapplicable;

� a batch number given at receipt;� where appropriate, the status of the contents (e.g. in quarantine, on test,

released, rejected);� where appropriate, an expiry date or a date beyond which retesting is

necessary.

When fully computerised storage systems are used, all the above informa-tion need not necessarily be in a legible form on the label.

5.30 There should be appropriate procedures or measures to assure the identityof the contents of each container of starting material. Bulk containers fromwhich samples have been drawn should be identified (see Section II, Chapter6, item 13).

5.31 Only starting materials which have been released by the Quality ControlDepartment and which are within their shelf life should be used.

5.32 Starting materials should only be dispensed by designated persons, follow-ing a written procedure, to ensure that the correct materials are accuratelyweighed or measured into clean and properly labelled containers.

5.33 Each dispensed material and its weight or volume should be independentlychecked and the check recorded.

5.34 Materials dispensed for each batch should be kept together and conspicu-ously labelled as such.


Processing Operations: intermediate and bulk products

5.35 Before any processing operation is started, steps should be taken to ensurethat the work area and equipment are clean and free from any startingmaterials, products, product residues or documents not required for thecurrent operation.

5.36 Intermediate and bulk products should be kept under appropriate condi-tions.

5.37 Critical processes should be validated (see “VALIDATION” in thischapter).

5.38 Any necessary in-process controls and environmental controls should becarried out and recorded.

5.39 Any significant deviation from the expected yield should be recorded andinvestigated.

Packaging Materials

5.40 The purchase, handling and control of primary and printed packagingmaterials shall be accorded attention similar to that given to starting ma-terials.

5.41 Particular attention should be paid to printed materials. They should bestored in adequately secure conditions such as to exclude unauthorisedaccess. Cut labels and other loose printed materials should be stored andtransported in separate closed containers so as to avoid mix-ups. Packagingmaterials should be issued for use only by authorised personnel followingan approved and documented procedure.

5.42 Each delivery or batch of printed or primary packaging material should begiven a specific reference number or identification mark.

5.43 Outdated or obsolete primary packaging material or printed packagingmaterial should be destroyed and this disposal recorded.

Packaging Operations

5.44 When setting up a programme for the packaging operations, particularattention should be given to minimising the risk of cross-contamination,mix-ups or substitutions. Different products should not be packaged inclose proximity unless there is physical segregation.


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5.45 Before packaging operations are begun, steps should be taken to ensure thatthe work area, packaging lines, printing machines and other equipment areclean and free from any products, materials or documents previously used,if these are not required for the current operation. The line-clearance shouldbe performed according to an appropriate check-list.

5.46 The name and batch number of the product being handled should be dis-played at each packaging station or line.

5.47 All products and packaging materials to be used should be checked ondelivery to the packaging department for quantity, identity and conformitywith the Packaging Instructions.

5.48 Containers for filling should be clean before filling. Attention should begiven to avoiding and removing any contaminants such as glass fragmentsand metal particles.

5.49 Normally, filling and sealing should be followed as quickly as possible bylabelling. If it is not the case, appropriate procedures should be applied toensure that no mix-ups or mislabelling can occur.

5.50 The correct performance of any printing operation (for example code num-bers, expiry dates) to be done separately or in the course of the packagingshould be checked and recorded. Attention should be paid to printing byhand which should be re-checked at regular intervals.

5.51 Special care should be taken when using cut-labels and when over-printingis carried out off-line. Roll-feed labels are normally preferable to cut-labels,in helping to avoid mix-ups.

5.52 Checks should be made to ensure that any electronic code readers, labelcounters or similar devices are operating correctly.

5.53 Printed and embossed information on packaging materials should be dis-tinct and resistant to fading or erasing.

5.54 On-line control of the product during packaging should include at leastchecking the following:

(a) general appearance of the packages;(b) whether the packages are complete;(c) whether the correct products and packaging materials are used;(d) whether any over-printing is correct;(e) correct functioning of line monitors.

Samples taken away from the packaging line should not be returned.

5.55 Products which have been involved in an unusual event should only bereintroduced into the process after special inspection, investigation and


approval by authorised personnel. Detailed record should be kept of thisoperation.

5.56 Any significant or unusual discrepancy observed during reconciliation ofthe amount of bulk product and printed packaging materials and the num-ber of units produced should be investigated and satisfactorily accountedfor before release.

5.57 Upon completion of a packaging operation, any unused batch-coded pack-aging materials should be destroyed and the destruction recorded. Adocumented procedure should be followed if uncoded printed materialsare returned to stock.

Finished Products

5.58 Finished products should be held in quarantine until their final releaseunder conditions established by the manufacturer.

5.59 The evaluation of finished products and documentation which is neces-sary before release of product for sale are described in Chapter 6 (QualityControl).

5.60 After release, finished products should be stored as usable stock underconditions established by the manufacturer.

Rejected, Recovered and Returned Materials

5.61 Rejected materials and products should be clearly marked as such andstored separately in restricted areas. They should either be returned to thesuppliers or, where appropriate, reprocessed or destroyed. Whatever actionis taken should be approved and recorded by authorised personnel.

5.62 The reprocessing of rejected products should be exceptional. It is only per-mitted if the quality of the final product is not affected, if the specificationsare met and if it is done in accordance with a defined and authorised pro-cedure after evaluation of the risks involved. Record should be kept of thereprocessing.

5.63 The recovery of all or part of earlier batches which conform to the requiredquality by incorporation into a batch of the same product at a defined stageof manufacture should be authorised beforehand. This recovery should becarried out in accordance with a defined procedure after evaluation ofthe risks involved, including any possible effect on shelf life. The recoveryshould be recorded.


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5.64 The need for additional testing of any finished product which has beenreprocessed, or into which a recovered product has been incorporated,should be considered by the Quality Control Department.

5.65 Products returned from the market and which have left the control ofthe manufacturer should be destroyed unless without doubt their quality issatisfactory; they may be considered for re-sale, re-labelling or recovery in asubsequent batch only after they have been critically assessed by the QualityControl Department in accordance with a written procedure. The natureof the product, any special storage conditions it requires, its condition andhistory, and the time elapsed since it was issued should all be taken intoaccount in this assessment. Where any doubt arises over the quality of theproduct, it should not be considered suitable for re-issue or re-use, althoughbasic chemical reprocessing to recover active ingredient may be possible.Any action taken should be appropriately recorded.


6 QUALITY CONTROL

Editor’snote

Came into force 1 June 2006.

Principle

Quality Control is concerned with sampling, specifications and testingas well as the organisation, documentation and release procedures whichensure that the necessary and relevant tests are carried out, and that ma-terials are not released for use, nor products released for sale or supply, untiltheir quality has been judged satisfactory. Quality Control is not confinedto laboratory operations, but must be involved in all decisions which mayconcern the quality of the product. The independence of Quality Controlfrom Production is considered fundamental to the satisfactory operationof Quality Control. (see also Section II, Chapter 1).

General

6.1 Each holder of a manufacturing authorisation should have a QualityControl Department. This department should be independent from otherdepartments, and under the authority of a person with appropriate qual-ifications and experience, who has one or several control laboratories athis disposal. Adequate resources must be available to ensure that all theQuality Control arrangements are effectively and reliably carried out.

6.2 The principal duties of the head of Quality Control are summarised inChapter 2. The Quality Control Department as a whole will also haveother duties, such as to establish, validate and implement all quality controlprocedures, keep the reference samples of materials and products, ensurethe correct labelling of containers of materials and products, ensure themonitoring of the stability of the products, participate in the investigationof complaints related to the quality of the product, etc. All these operationsshould be carried out in accordance with written procedures and, wherenecessary, recorded.

6.3 Finished product assessment should embrace all relevant factors, includ-ing production conditions, results of in-process testing, a review of manu-facturing (including packaging) documentation, compliance with FinishedProduct Specification and examination of the final finished pack.


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6.4 Quality Control personnel should have access to production areas for sam-pling and investigation as appropriate.

Good Quality Control Laboratory Practice

6.5 Control laboratory premises and equipment should meet the general andspecific requirements for Quality Control areas given in Chapter 3.

6.6 The personnel, premises, and equipment in the laboratories should beappropriate to the tasks imposed by the nature and the scale of the manu-facturing operations. The use of outside laboratories, in conformity withthe principles detailed in Chapter 7, Contract Analysis, can be acceptedfor particular reasons, but this should be stated in the Quality Controlrecords.

Documentation

6.7 Laboratory documentation should follow the principles given in Chapter 4.An important part of this documentation deals with Quality Control andthe following details should be readily available to the Quality ControlDepartment:

� specifications;� sampling procedures;� testing procedures and records (including analytical worksheets and/or

laboratory notebooks);� analytical reports and/or certificates;� data from environmental monitoring, where required;� validation records of test methods, where applicable;� procedures for and records of the calibration of instruments and main-

tenance of equipment.

6.8 Any Quality Control documentation relating to a batch record shouldbe retained for one year after the expiry date of the batch and at least5 years after the certification referred to in Article 51(3) of Directive 2001/83/EC.

6.9 For some kinds of data (e.g. analytical tests results, yields, environmentalcontrols) it is recommended that records are kept in a manner permittingtrend evaluation.

6.10 In addition to the information which is part of the batch record, other orig-inal data such as laboratory notebooks and/or records should be retainedand readily available.


Sampling

6.11 The sample taking should be done in accordance with approved writtenprocedures that describe:

� the method of sampling;� the equipment to be used;� the amount of the sample to be taken;� instructions for any required sub-division of the sample;� the type and condition of the sample container to be used;� the identification of containers sampled;� any special precautions to be observed, especially with regard to the

sampling of sterile or noxious materials;� the storage conditions;� instructions for the cleaning and storage of sampling equipment.

6.12 Reference samples should be representative of the batch of materials orproducts from which they are taken. Other samples may also be taken tomonitor the most stressed part of a process (e.g. beginning or end of aprocess).

6.13 Sample containers should bear a label indicating the contents, with thebatch number, the date of sampling and the containers from which sampleshave been drawn.

6.14 Further guidance on reference and retention samples is given in Annex 19.

Testing

6.15 Analytical methods should be validated. All testing operations describedin the marketing authorisation should be carried out according to theapproved methods.

6.16 The results obtained should be recorded and checked to make sure thatthey are consistent with each other. Any calculations should be criticallyexamined.

6.17 The tests performed should be recorded and the records should include atleast the following data:

(a) name of the material or product and, where applicable, dosage form;(b) batch number and, where appropriate, the manufacturer and/or sup-

plier;(c) references to the relevant specifications and testing procedures;(d) test results, including observations and calculations, and reference to

any certificates of analysis;(e) dates of testing;


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(f) initials of the persons who performed the testing;(g) initials of the persons who verified the testing and the calculations,

where appropriate;(h) a clear statement of release or rejection (or other status decision) and

the dated signature of the designated responsible person.

6.18 All the in-process controls, including those made in the production areaby production personnel, should be performed according to methodsapproved by Quality Control and the results recorded.

6.19 Special attention should be given to the quality of laboratory reagents,volumetric glassware and solutions, reference standards and culture media.They should be prepared in accordance with written procedures.

6.20 Laboratory reagents intended for prolonged use should be marked with thepreparation date and the signature of the person who prepared them. Theexpiry date of unstable reagents and culture media should be indicatedon the label, together with specific storage conditions. In addition, forvolumetric solutions, the last date of standardisation and the last currentfactor should be indicated.

6.21 Where necessary, the date of receipt of any substance used for testing oper-ations (e.g. reagents and reference standards) should be indicated on thecontainer. Instructions for use and storage should be followed. In certaincases it may be necessary to carry out an identification test and/or othertesting of reagent materials upon receipt or before use.

6.22 Animals used for testing components, materials or products, should, whereappropriate, be quarantined before use. They should be maintained andcontrolled in a manner that assures their suitability for the intended use.They should be identified, and adequate records should be maintained,showing the history of their use.

On-going stability programme

6.23 After marketing, the stability of the medicinal product should be moni-tored according to a continuous appropriate programme that will permitthe detection of any stability issue (e.g. changes in levels of impurities or dis-solution profile) associated with the formulation in the marketed package.

6.24 The purpose of the on-going stability programme is to monitor theproduct over its shelf life and to determine that the product remains, andcan be expected to remain, within specifications under the labelled storageconditions.

6.25 This mainly applies to the medicinal product in the package in whichit is sold, but consideration should also be given to the inclusion in the


programme of bulk product. For example, when the bulk product isstored for a long period before being packaged and/or shipped from amanufacturing site to a packaging site, the impact on the stability ofthe packaged product should be evaluated and studied under ambientconditions. In addition, consideration should be given to intermediatesthat are stored and used over prolonged periods. Stability studies onreconstituted product are performed during product development andneed not be monitored on an on-going basis. However, when relevant, thestability of reconstituted product can also be monitored.

6.26 The on-going stability programme should be described in a writtenprotocol following the general rules of Chapter 4 and results formalisedas a report. The equipment used for the on-going stability programme(stability chambers among others) should be qualified and maintainedfollowing the general rules of Chapter 3 and Annex 15.

6.27 The protocol for an on-going stability programme should extend to theend of the shelf life period and should include, but not be limited to, thefollowing parameters:

� number of batch(es) per strength and different batch sizes, if appli-cable;

� relevant physical, chemical, microbiological and biological testmethods;

� acceptance criteria;� reference to test methods;� description of the container closure system(s);� testing intervals (time points);� description of the conditions of storage (standardised ICH conditions for

long-term testing, consistent with the product labelling, should be used);� other applicable parameters specific to the medicinal product.

6.28 The protocol for the on-going stability programme can be different fromthat of the initial long-term stability study as submitted in the marketingauthorisation dossier provided that this is justified and documented in theprotocol (for example the frequency of testing, or when updating to ICHrecommendations).

6.29 The number of batches and frequency of testing should provide a sufficientamount of data to allow for trend analysis. Unless otherwise justified,at least one batch per year of product manufactured in every strengthand every primary packaging type, if relevant, should be included in thestability programme (unless none are produced during that year). Forproducts where on-going stability monitoring would normally requiretesting using animals and no appropriate alternative, validated techniquesare available, the frequency of testing may take account of a risk-benefit


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approach. The principle of bracketing and matrixing designs may beapplied if scientifically justified in the protocol.

6.30 In certain situations, additional batches should be included in the on-goingstability programme. For example, an on-going stability study shouldbe conducted after any significant change or significant deviation to theprocess or package. Any reworking, reprocessing or recovery operationshould also be considered for inclusion.

6.31 Results of on-going stability studies should be made available to keypersonnel and, in particular, to the Qualified Person(s). Where on-goingstability studies are carried out at a site other than the site of manufacture ofthe bulk or finished product, there should be a written agreement betweenthe parties concerned. Results of on-going stability studies should beavailable at the site of manufacture for review by the competent authority.

6.32 Out of specification or significant atypical trends should be investigated.Any confirmed out of specification result, or significant negative trend,should be reported to the relevant competent authorities. The possibleimpact on batches on the market should be considered in accordancewith Chapter 8 of the GMP Guide and in consultation with the relevantcompetent authorities.

6.33 A summary of all the data generated, including any interim conclusions onthe programme, should be written and maintained. This summary shouldbe subjected to periodic review.


7 CONTRACT MANUFACTURE AND ANALYSIS

Principle

Contract manufacture and analysis must be correctly defined, agreed andcontrolled in order to avoid misunderstandings which could result in aproduct or work of unsatisfactory quality. There must be a written con-tract between the Contract Giver and the Contract Acceptor which clearlyestablishes the duties of each party. The contract must clearly state theway in which the Qualified Person releasing each batch of product for saleexercises his full responsibility.

Note: This chapter deals with the responsibilities of manufacturerstowards the Competent Authorities of the Member States with respectto the granting of marketing and manufacturing authorisations. It is notintended in any way to affect the respective liability of contract acceptorsand contract givers to consumers; this is governed by other provisions ofCommunity and national law.

General

7.1 There should be a written contract covering the manufacture and/oranalysis arranged under contract and any technical arrangements madein connection with it.

7.2 All arrangements for contract manufacture and analysis including any pro-posed changes in technical or other arrangements should be in accordancewith the marketing authorisation for the product concerned.

The Contract Giver

7.3 The Contract Giver is responsible for assessing the competence of the Con-tract Acceptor to carry out successfully the work required and for ensuringby means of the contract that the principles and guidelines of GMP asinterpreted in this Guide are followed.

7.4 The Contract Giver should provide the Contract Acceptor with all theinformation necessary to carry out the contracted operations correctly inaccordance with the marketing authorisation and any other legal require-ments. The Contract Giver should ensure that the Contract Acceptor isfully aware of any problems associated with the product or the work whichmight pose a hazard to his premises, equipment, personnel, other materialsor other products.


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7.5 The Contract Giver should ensure that all processed products and materialsdelivered to him by the Contract Acceptor comply with their specificationsor that the products have been released by a Qualified Person.

The Contract Acceptor

7.6 The Contract Acceptor must have adequate premises and equipment,knowledge and experience, and competent personnel to carry out satis-factorily the work ordered by the Contract Giver. Contract manufacturemay be undertaken only by a manufacturer who is the holder of a manu-facturing authorisation.

7.7 The Contract Acceptor should ensure that all products or materials deliv-ered to him are suitable for their intended purpose.

7.8 The Contract Acceptor should not pass to a third party any of the workentrusted to him under the contract without the Contract Giver’s priorevaluation and approval of the arrangements. Arrangements made betweenthe Contract Acceptor and any third party should ensure that the manu-facturing and analytical information is made available in the same way asbetween the original Contract Giver and Contract Acceptor.

7.9 The Contract Acceptor should refrain from any activity which mayadversely affect the quality of the product manufactured and/or analysedfor the Contract Giver.

The Contract

7.10 A contract should be drawn up between the Contract Giver and the Con-tract Acceptor which specifies their respective responsibilities relating tothe manufacture and control of the product. Technical aspects of the con-tract should be drawn up by competent persons suitably knowledgeablein pharmaceutical technology, analysis and Good Manufacturing Practice.All arrangements for manufacture and analysis must be in accordance withthe marketing authorisation and agreed by both parties.

7.11 The contract should specify the way in which the Qualified Person releasingthe batch for sale ensures that each batch has been manufactured andchecked for compliance with the requirements of Marketing Authorisation.

7.12 The contract should describe clearly who is responsible for purchasingmaterials, testing and releasing materials, undertaking production andquality controls, including in-process controls, and who has responsibilityfor sampling and analysis. In the case of contract analysis, the contract


should state whether or not the Contract Acceptor should take samples atthe premises of the manufacturer.

7.13 Manufacturing, analytical and distribution records, and reference samplesshould be kept by, or be available to, the Contract Giver. Any recordsrelevant to assessing the quality of a product in the event of complaintsor a suspected defect must be accessible and specified in the defect/recallprocedures of the Contract Giver.

7.14 The contract should permit the Contract Giver to visit the facilities of theContract Acceptor.

7.15 In the case of contract analysis, the Contract Acceptor should understandthat he is subject to Inspection by the competent Authorities.


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8 COMPLAINTS AND PRODUCT RECALL

Editor’snote

Revised December 2005, came into operation February 2006.

Principle

All complaints and other information concerning potentially defectiveproducts must be reviewed carefully according to written procedures. Inorder to provide for all contingencies, and in accordance with Article 117of Directive 2001/83/EC and Article 84 of Directive 2001/82/EC, a systemshould be designed to recall, if necessary, promptly and effectively productsknown or suspected to be defective from the market.

Complaints

8.1 A person should be designated responsible for handling the complaints anddeciding the measures to be taken together with sufficient supporting staffto assist him. If this person is not the Qualified Person, the latter should bemade aware of any complaint, investigation or recall.

8.2 There should be written procedures describing the action to be taken,including the need to consider a recall, in the case of a complaint con-cerning a possible product defect.

8.3 Any complaint concerning a product defect should be recorded with allthe original details and thoroughly investigated. The person responsible forQuality Control should normally be involved in the study of such problems.

8.4 If a product defect is discovered or suspected in a batch, considerationshould be given to checking other batches in order to determine whetherthey are also affected. In particular, other batches which may containreworks of the defective batch should be investigated.

8.5 All the decisions and measures taken as a result of a complaint should berecorded and referenced to the corresponding batch records.

8.6 Complaints records should be reviewed regularly for any indication ofspecific or recurring problems requiring attention and possibly the recallof marketed products.

8.7 Special attention should be given to establishing whether a complaint wascaused because of counterfeiting.


8.8 The competent authorities should be informed if a manufacturer is consid-ering action following possibly faulty manufacture, product deterioration,detection of counterfeiting or any other serious quality problems with aproduct.

Recalls

8.9 A person should be designated as responsible for execution and co-ordination of recalls and should be supported by sufficient staff to handleall the aspects of the recalls with the appropriate degree of urgency. Thisresponsible person should normally be independent of the sales and mar-keting organisation. If this person is not the Qualified Person, the lattershould be made aware of any recall operation.

8.10 There should be established written procedures, regularly checked andupdated when necessary, in order to organise any recall activity.

8.11 Recall operations should be capable of being initiated promptly and at anytime.

8.12 All Competent Authorities of all countries to which products may havebeen distributed should be informed promptly if products are intended tobe recalled because they are, or are suspected of being defective.

8.13 The distribution records should be readily available to the person(s) respon-sible for recalls, and should contain sufficient information on wholesalersand directly supplied customers (with addresses, phone and/or fax num-bers inside and outside working hours, batches and amounts delivered),including those for exported products and medical samples.

8.14 Recalled products should be identified and stored separately in a securearea while awaiting a decision on their fate.

8.15 The progress of the recall process should be recorded and a final reportissued, including a reconciliation between the delivered and recoveredquantities of the products.

8.16 The effectiveness of the arrangements for recalls should be evaluatedregularly.


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9 SELF INSPECTION

Principle

Self inspections should be conducted in order to monitor the implementa-tion and compliance with Good Manufacturing Practice principles and topropose necessary corrective measures.

9.1 Personnel matters, premises, equipment, documentation, production, qual-ity control, distribution of the medicinal products, arrangements for deal-ing with complaints and recalls, and self inspection, should be examinedat intervals following a pre-arranged programme in order to verify theirconformity with the principles of Quality Assurance.

9.2 Self inspections should be conducted in an independent and detailed wayby designated competent person(s) from the company. Independent auditsby external experts may also be useful.

9.3 All self inspections should be recorded. Reports should contain all theobservations made during the inspections and, where applicable, propos-als for corrective measures. Statements on the actions subsequently takenshould also be recorded.


ANNEX 1 MANUFACTURE OF STERILE MEDICINAL PRODUCTS

Note: Annex 1 of the EU Guide to Good Manufacturing Practice (GMP)provides supplementary guidance on the application of the principles andguidelines of GMP to sterile medicinal products. The guidance includes rec-ommendations on standards of environmental cleanliness for clean rooms.The guidance has been reviewed in the light of the international standardEN/ISO 14644-1 and amended in the interests of harmonisation but takinginto account specific concerns unique to the production of sterile medicinalproducts.

The changes affect Section 3 of the annex together with a minor changeto Section 20. The remainder of the annex remains unchanged.

Principle

The manufacture of sterile products is subject to special requirements inorder to minimise risks of microbiological contamination, and of partic-ulate and pyrogen contamination. Much depends on the skill, trainingand attitudes of the personnel involved. Quality Assurance is particularlyimportant, and this type of manufacture must strictly follow carefullyestablished and validated methods of preparation and procedure. Solereliance for sterility or other quality aspects must not be placed on anyterminal process or finished product test.

Note: This guidance does not lay down detailed methods for determiningthe microbiological and particulate cleanliness of air, surfaces, etc. Refer-ence should be made to other documents such as the EN/ISO Standards.

General

1 The manufacture of sterile products should be carried out in clean areasentry to which should be through airlocks for personnel and/or for equip-ment and materials. Clean areas should be maintained to an appropriatecleanliness standard and supplied with air which has passed through filtersof an appropriate efficiency.

2 The various operations of component preparation, product preparationand filling should be carried out in separate areas within the clean area.Manufacturing operations are divided into two categories; firstly thosewhere the product is terminally sterilised, and secondly those which areconducted aseptically at some or all stages.

3 Clean areas for the manufacture of sterile products are classified accordingto the required characteristics of the environment. Each manufacturing


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operation requires an appropriate environmental cleanliness level in theoperational state in order to minimise the risks of particulate or microbialcontamination of the product or materials being handled.

In order to meet “in operation” conditions these areas should be designedto reach certain specified air-cleanliness levels in the “at rest” occupancystate. The “at-rest” state is the condition where the installation is installedand operating, complete with production equipment but with no operatingpersonnel present. The “in operation” state is the condition where theinstallation is functioning in the defined operating mode with the specifiednumber of personnel working.

The “in operation” and “at rest” states should be defined for each cleanroom or suite of clean rooms. For the manufacture of sterile medicinalproducts 4 grades can be distinguished:

Grade A: The local zone for high risk operations, e.g. filling zone,stopper bowls, open ampoules and vials, making asepticconnections. Normally such conditions are provided by alaminar air flow work station. Laminar air flow systemsshould provide a homogeneous air speed in a range of0.36–0.54 m/s (guidance value) at the working positionin open clean room applications. The maintenance oflaminarity should be demonstrated and validated. A uni-directional air flow and lower velocities may be used inclosed isolators and glove boxes.

Grade B: For aseptic preparation and filling, this is the backgroundenvironment for the grade A zone.

Grade C and D: Clean areas for carrying out less critical stages in themanufacture of sterile products. The airborne particulateclassification for these grades is given in the followingtable.

at rest (b) in operation (b)

Grade maximum permitted number of particles/m3 equal to or above (a)

0.5 µm (d) 5 µm 0.5 µm (d) 5 µmA 3 500 1(e) 3 500 1(e)B (c) 3 500 1(e) 350 000 2 000C (c) 350 000 2 000 3 500 000 20 000D (c) 3 500 000 20 000 not defined ( f ) Not defined ( f )

Notes:(a) Particle measurement based on the use of a discrete airborne particle counter tomeasure the concentration of particles at designated sizes equal to or greater than thethreshold stated. A continuous measurement system should be used for monitoring theconcentration of particles in the grade A zone, and is recommended for the surroundinggrade B areas.

For routine testing the total sample volume should not be less than 1 m3 for grade Aand B areas and preferably also in grade C areas.


(b) The particulate conditions given in the table for the “at rest” state should be achievedafter a short “clean up” period of 15–20 minutes (guidance value) in an unmanned stateafter completion of operations.

The particulate conditions for grade A “in operation” given in the table should bemaintained in the zone immediately surrounding the product whenever the product oropen container is exposed to the environment. It is accepted that it may not always bepossible to demonstrate conformity with particulate standards at the point of fill whenfilling is in progress, due to the generation of particles or droplets from the product itself.(c) In order to reach the B, C and D air grades, the number of air changes should berelated to the size of the room and the equipment and personnel present in the room. Theair system should be provided with appropriate terminal filters such as HEPA for gradesA, B and C.(d) The guidance given for the maximum permitted number of particles in the “at rest”and “in operation” conditions correspond approximately to the cleanliness classes in theEN/ISO 14644-1 at a particle size of 0.5 µm.(e) These areas are expected to be completely free from particles of size greater than orequal to 5 µm. As it is impossible to demonstrate the absence of particles with any sta-tistical significance the limits are set to 1 particle/m3. During the clean room qualificationit should be shown that the areas can be maintained within the defined limits.(f) The requirements and limits will depend on the nature of the operations carried out.Other characteristics such as temperature and relative humidity depend on the productand nature of the operations carried out. These parameters should not interfere with thedefined cleanliness standard.

Examples of operations to be carried out in the various grades are given inthe table below. (see also par. 11 and par.12)

Grade Examples of operations for terminally sterilised products. (see par. 11)A Filling of products, when unusually at riskC Preparation of solutions, when unusually at risk. Filling of productsD Preparation of solutions and components for subsequent filling

Grade Examples of operations for aseptic preparations. (see par. 12)A Aseptic preparation and fillingC Preparation of solutions to be filteredD Handling of components after washing

4 The areas should be monitored during operation, in order to control theparticulate cleanliness of the various grades.

5 Where aseptic operations are performed monitoring should be frequentusing methods such as settle plates, volumetric air and surface sampling(e.g. swabs and contact plates). Sampling methods used in operation shouldnot interfere with zone protection. Results from monitoring should be con-sidered when reviewing batch documentation for finished product release.Surfaces and personnel should be monitored after critical operations.

Additional microbiological monitoring is also required outside produc-tion operations, e.g. after validation of systems, cleaning and sanitisation.

Recommended limits for microbiological monitoring of clean areas dur-ing operation.


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Recommended limits for microbial contamination (a)

settle plates contact plates glove printair sample (diam. 90 mm), (diam. 55 mm), 5 fingers

Grade cfu/m3 cfu/4 hours (b) cfu/plate cfu/glove

A < 1 < 1 < 1 < 1B 10 5 5 5C 100 50 25 –D 200 100 50 –

Notes:(a) These are average values.(b) Individual settle plates may be exposed for less than 4 hours.

6 Appropriate alert and action limits should be set for the results of particu-late and microbiological monitoring. If these limits are exceeded operatingprocedures should prescribe corrective action.

Isolator Technology

7 The utilisation of isolator technology to minimise human interventions inprocessing areas may result in a significant decrease in the risk of micro-biological contamination of aseptically manufactured products from theenvironment. There are many possible designs of isolators and trans-fer devices. The isolator and the background environment should bedesigned so that the required air quality for the respective zones can berealised. Isolators are constructed of various materials more or less proneto puncture and leakage. Transfer devices may vary from a single doorto double door designs to fully sealed systems incorporating sterilisationmechanisms.

The transfer of materials into and out of the unit is one of the great-est potential sources of contamination. In general the area inside theisolator is the local zone for high risk manipulations, although it is recog-nised that laminar air flow may not exist in the working zone of all suchdevices.

The air classification required for the background environment dependson the design of the isolator and its application. It should be controlledand for aseptic processing it should be at least grade D.

8 Isolators should be introduced only after appropriate validation. Valida-tion should take into account all critical factors of isolator technology, forexample the quality of the air inside and outside (background) the isolator,sanitisation of the isolator, the transfer process and isolator integrity.

9 Monitoring should be carried out routinely and should include frequentleak testing of the isolator and glove/sleeve system.


Blow/Fill/Seal Technology

10 Blow/fill/seal units are purpose built machines in which, in one continuousoperation, containers are formed from a thermoplastic granulate, filledand then sealed, all by the one automatic machine. Blow/fill/seal equip-ment used for aseptic production which is fitted with an effective gradeA air shower may be installed in at least a grade C environment, pro-vided that grade A/B clothing is used. The environment should complywith the viable and non viable limits at rest and the viable limit only whenin operation. Blow/fill/seal equipment used for the production of productswhich are terminally sterilised should be installed in at least a grade Denvironment.

Because of this special technology particular attention should be paid to,at least the following: equipment design and qualification, validation andreproducibility of cleaning-in-place and sterilisation-in-place, backgroundcleanroom environment in which the equipment is located, operatortraining and clothing, and interventions in the critical zone of the equip-ment including any aseptic assembly prior to the commencement of filling.

Terminally Sterilised Products

11 Preparation of components and most products should be done in at least agrade D environment in order to give low risk of microbial and particulatecontamination, suitable for filtration and sterilisation. Where the product isat a high or unusual risk of microbial contamination, (for example, becausethe product actively supports microbial growth or must be held for a longperiod before sterilisation or is necessarily processed not mainly in closedvessels), then preparation should be carried out in a grade C environment.

Filling of products for terminal sterilisation should be carried out in atleast a grade C environment.

Where the product is at unusual risk of contamination from the environ-ment, for example because the filling operation is slow or the containers arewide-necked or are necessarily exposed for more than a few seconds beforesealing, the filling should be done in a grade A zone with at least a gradeC background. Preparation and filling of ointments, creams, suspensionsand emulsions should generally be carried out in a grade C environmentbefore terminal sterilisation.

Aseptic Preparation

12 Components after washing should be handled in at least a grade D envir-onment. Handling of sterile starting materials and components, unless


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subjected to sterilisation or filtration through a micro-organism-retainingfilter later in the process, should be done in a grade A environment withgrade B background. Preparation of solutions which are to be sterile fil-tered during the process should be done in a grade C environment; if notfiltered, the preparation of materials and products should be done in agrade A environment with a grade B background.

Handling and filling of aseptically prepared products should be done ina grade A environment with a grade B background.

Prior to the completion of stoppering, transfer of partially closed con-tainers, as used in freeze drying should be done either in a grade A envir-onment with grade B background or in sealed transfer trays in a grade Benvironment.

Preparation and filling of sterile ointments, creams, suspensions andemulsions should be done in a grade A environment, with a grade B back-ground, when the product is exposed and is not subsequently filtered.

Personnel

13 Only the minimum number of personnel required should be present in cleanareas; this is particularly important during aseptic processing. Inspectionsand controls should be conducted outside the clean areas as far as possible.

14 All personnel (including those concerned with cleaning and maintenance)employed in such areas should receive regular training in disciplines rele-vant to the correct manufacture of sterile products. This training shouldinclude reference to hygiene and to the basic elements of microbiology.When outside staff who have not received such training (e.g. building ormaintenance contractors) need to be brought in, particular care should betaken over their instruction and supervision.

15 Staff who have been engaged in the processing of animal tissue materials orof cultures of micro-organisms other than those used in the current manu-facturing process should not enter sterile-product areas unless rigorous andclearly defined entry procedures have been followed.

16 High standards of personal hygiene and cleanliness are essential. Personnelinvolved in the manufacture of sterile preparations should be instructed toreport any condition which may cause the shedding of abnormal numbersor types of contaminants; periodic health checks for such conditions aredesirable. Actions to be taken about personnel who could be introducingundue microbiological hazard should be decided by a designated competentperson.

17 Changing and washing should follow a written procedure designed to min-imise contamination of clean area clothing or carry-through of contam-inants to the clean areas.


18 Wristwatches, make-up and jewellery should not be worn in clean areas.

19 The clothing and its quality should be appropriate for the process and thegrade of the working area. It should be worn in such a way as to protectthe product from contamination.

The description of clothing required for each grade is given below:

Grade D: Hair and, where relevant, beard should be covered. A generalprotective suit and appropriate shoes or overshoes should beworn. Appropriate measures should be taken to avoid anycontamination coming from outside the clean area.

Grade C: Hair and where relevant beard and moustache should be cov-ered. A single or two-piece trouser suit, gathered at the wristsand with high neck and appropriate shoes or overshoes shouldbe worn. They should shed virtually no fibres or particulatematter.

Grade A/B: Headgear should totally enclose hair and, where relevant,beard and moustache; it should be tucked into the neck ofthe suit; a face mask should be worn to prevent the sheddingof droplets. Appropriate sterilised, non-powdered rubber orplastic gloves and sterilised or disinfected footwear should beworn. Trouser-legs should be tucked inside the footwear andgarment sleeves into the gloves. The protective clothing shouldshed virtually no fibres or particulate matter and retain parti-cles shed by the body.

20 Outdoor clothing should not be brought into changing rooms leading tograde B and C rooms. For every worker in a grade A/B area, clean sterile(sterilised or adequately sanitised) protective garments should be providedat each work session. Gloves should be regularly disinfected during oper-ations.

Masks and gloves should be changed at least for every working session.

21 Clean area clothing should be cleaned and handled in such a way that itdoes not gather additional contaminants which can later be shed. Theseoperations should follow written procedures. Separate laundry facilitiesfor such clothing are desirable. Inappropriate treatment of clothing willdamage fibres and may increase the risk of shedding of particles.

Premises

22 In clean areas, all exposed surfaces should be smooth, impervious andunbroken in order to minimise the shedding or accumulation of particlesor micro-organisms and to permit the repeated application of cleaningagents, and disinfectants where used.


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23 To reduce accumulation of dust and to facilitate cleaning there should beno uncleanable recesses and a minimum of projecting ledges, shelves, cup-boards and equipment. Doors should be designed to avoid those unclean-able recesses; sliding doors may be undesirable for this reason.

24 False ceilings should be sealed to prevent contamination from the spaceabove them.

25 Pipes and ducts and other utilities should be installed so that they do notcreate recesses, unsealed openings and surfaces which are difficult to clean.

26 Sinks and drains should be prohibited in grade A/B areas used for asepticmanufacture. In other areas air breaks should be fitted between the machineor sink and the drains. Floor drains in lower grade clean rooms should befitted with traps or water seals to prevent back-flow.

27 Changing rooms should be designed as airlocks and used to providephysical separation of the different stages of changing and so minimisemicrobial and particulate contamination of protective clothing. Theyshould be flushed effectively with filtered air. The final stage of the chang-ing room should, in the at-rest state, be the same grade as the area intowhich it leads.

The use of separate changing rooms for entering and leaving clean areas issometimes desirable. In general hand washing facilities should be providedonly in the first stage of the changing rooms.

28 Both airlock doors should not be opened simultaneously. An interlockingsystem or a visual and/or audible warning system should be operated toprevent the opening of more than one door at a time.

29 A filtered air supply should maintain a positive pressure and an air flow rel-ative to surrounding areas of a lower grade under all operational conditionsand should flush the area effectively. Adjacent rooms of different gradesshould have a pressure differential of 10–15 pascals (guidance values). Par-ticular attention should be paid to the protection of the zone of greatestrisk, that is, the immediate environment to which a product and cleanedcomponents which contact the product are exposed. The various recom-mendations regarding air supplies and pressure differentials may need tobe modified where it becomes necessary to contain some materials, e.g.pathogenic, highly toxic, radioactive or live viral or bacterial materials orproducts. Decontamination of facilities and treatment of air leaving a cleanarea may be necessary for some operations.

30 It should be demonstrated that air-flow patterns do not present a con-tamination risk, e.g. care should be taken to ensure that air flows do notdistribute particles from a particle-generating person, operation or machineto a zone of higher product risk.


31 A warning system should be provided to indicate failure in the air sup-ply. Indicators of pressure differences should be fitted between areaswhere these differences are important. These pressure differences shouldbe recorded regularly or otherwise documented.

Equipment

32 A conveyor belt should not pass through a partition between a grade A orB area and a processing area of lower air cleanliness, unless the belt itselfis continually sterilised (e.g. in a sterilising tunnel).

33 As far as practicable equipment, fittings and services should be designedand installed so that operations, maintenance and repairs can be carriedout outside the clean area. If sterilisation is required, it should be carriedout, wherever possible, after complete reassembly.

34 When equipment maintenance has been carried out within the clean area,the area should be cleaned, disinfected and/or sterilised where appropriate,before processing recommences if the required standards of cleanlinessand/or asepsis have not been maintained during the work.

35 Water treatment plants and distribution systems should be designed, con-structed and maintained so as to ensure a reliable source of water of anappropriate quality. They should not be operated beyond their designedcapacity. Water for injections should be produced, stored and distributedin a manner which prevents microbial growth, for example by constantcirculation at a temperature above 70◦C.

36 All equipment such as sterilisers, air handling and filtration systems, airvent and gas filters, water treatment, generation, storage and distributionsystems should be subject to validation and planned maintenance; theirreturn to use should be approved.

Sanitation

37 The sanitation of clean areas is particularly important. They should becleaned thoroughly in accordance with a written programme. Where dis-infectants are used, more than one type should be employed. Monitoringshould be undertaken regularly in order to detect the development of resis-tant strains.

38 Disinfectants and detergents should be monitored for microbial contamin-ation; dilutions should be kept in previously cleaned containers and


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should only be stored for defined periods unless sterilised. Disinfectantsand detergents used in grades A and B areas should be sterile prior touse.

39 Fumigation of clean areas may be useful for reducing microbiological con-tamination in inaccessible places.

Processing

40 Precautions to minimise contamination should be taken during all process-ing stages including the stages before sterilisation.

41 Preparations of microbiological origin should not be made or filled in areasused for the processing of other medicinal products; however, vaccines ofdead organisms or of bacterial extracts may be filled, after inactivation, inthe same premises as other sterile medicinal products.

42 Validation of aseptic processing should include a process simulation testusing a nutrient medium (media fill). Selection of the nutrient mediumshould be made based on dosage form of the product and selectiv-ity, clarity, concentration and suitability for sterilisation of the nutrientmedium. The process simulation test should imitate as closely as possi-ble the routine aseptic manufacturing process and include all the crit-ical subsequent manufacturing steps. It should also take into accountvarious interventions known to occur during normal production as wellas worst case situations. Process simulation tests should be performedas initial validation with three consecutive satisfactory simulation testsper shift and repeated at defined intervals and after any significantmodification to the HVAC-system, equipment, process and number ofshifts.

Normally process simulation tests should be repeated twice a year pershift and process. The number of containers used for media fills shouldbe sufficient to enable a valid evaluation. For small batches, the numberof containers for media fills should at least equal the size of the productbatch. The target should be zero growth but a contamination rate of lessthan 0.1% with 95% confidence limit is acceptable. The manufacturershould establish alert and action limits.

Any contamination should be investigated.

43 Care should be taken that any validation does not compromise theprocesses.

44 Water sources, water treatment equipment and treated water should bemonitored regularly for chemical and biological contamination and, as


appropriate, for endotoxins. Records should be maintained of the resultsof the monitoring and of any action taken.

45 Activities in clean areas and especially when aseptic operations are inprogress should be kept to a minimum and movement of personnel shouldbe controlled and methodical, to avoid excessive shedding of particles andorganisms due to over-vigorous activity. The ambient temperature andhumidity should not be uncomfortably high because of the nature of thegarments worn.

46 Microbiological contamination of starting materials should be minimal.Specifications should include requirements for microbiological qualitywhen the need for this has been indicated by monitoring.

47 Containers and materials liable to generate fibres should be minimised inclean areas.

48 Where appropriate, measures should be taken to minimise the particulatecontamination of the end product.

49 Components, containers and equipment should be handled after the finalcleaning process in such a way that they are not recontaminated.

50 The interval between the washing and drying and the sterilisation of com-ponents, containers and equipment as well as between their sterilisationand use should be minimised and subject to a time-limit appropriate to thestorage conditions.

51 The time between the start of the preparation of a solution and its ster-ilisation or filtration through a micro-organism-retaining filter should beminimised. There should be a set maximum permissible time for each prod-uct that takes into account its composition and the prescribed method ofstorage.

52 The bioburden should be monitored before sterilisation. There shouldbe working limits on contamination immediately before sterilisationwhich are related to the efficiency of the method to be used. Whereappropriate the absence of pyrogens should be monitored. All solutions,in particular large volume infusion fluids, should be passed througha micro-organism-retaining filter, if possible sited immediately beforefilling.

53 Components, containers, equipment and any other article required in aclean area where aseptic work takes place should be sterilised and passedinto the area through double-ended sterilisers sealed into the wall, or by aprocedure which achieves the same objective of not introducing contam-ination. Non-combustible gases should be passed through micro-organism-retentive filters.


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54 The efficacy of any new procedure should be validated, and the validationverified at scheduled intervals based on performance history or when anysignificant change is made in the process or equipment.

Sterilisation

55 All sterilisation processes should be validated. Particular attention shouldbe given when the adopted sterilisation method is not described in the cur-rent edition of the European Pharmacopoeia, or when it is used for a prod-uct which is not a simple aqueous or oily solution. Where possible, heat ster-ilisation is the method of choice. In any case, the sterilisation process mustbe in accordance with the marketing and manufacturing authorisations.

56 Before any sterilisation process is adopted its suitability for the productand its efficacy in achieving the desired sterilising conditions in all partsof each type of load to be processed should be demonstrated by physicalmeasurements and by biological indicators where appropriate. Thevalidity of the process should be verified at scheduled intervals, at leastannually, and whenever significant modifications have been made to theequipment. Records should be kept of the results.

57 For effective sterilisation the whole of the material must be subjected tothe required treatment and the process should be designed to ensure thatthis is achieved.

58 Validated loading patterns should be established for all sterilisationprocesses.

59 Biological indicators should be considered as an additional method formonitoring the sterilisation. They should be stored and used accordingto the manufacturers instructions, and their quality checked by positivecontrols. If biological indicators are used, strict precautions should betaken to avoid transferring microbial contamination from them.

60 There should be a clear means of differentiating products which havenot been sterilised from those which have. Each basket, tray or othercarrier of products or components should be clearly labelled with thematerial name, its batch number and an indication of whether or not ithas been sterilised. Indicators such as autoclave tape may be used, whereappropriate, to indicate whether or not a batch (or sub-batch) has passedthrough a sterilisation process, but they do not give a reliable indicationthat the lot is, in fact, sterile.

61 Sterilisation records should be available for each sterilisation run. Theyshould be approved as part of the batch release procedure.


Sterilisation by Heat

62 Each heat sterilisation cycle should be recorded on a time/temperature chartwith a sufficiently large scale or by other appropriate equipment with suit-able accuracy and precision. The position of the temperature probes usedfor controlling and/or recording should have been determined during thevalidation, and where applicable also checked against a second indepen-dent temperature probe located at the same position.

63 Chemical or biological indicators may also be used, but should not takethe place of physical measurements.

64 Sufficient time must be allowed for the whole of the load to reach therequired temperature before measurement of the sterilising time-period iscommenced. This time must be determined for each type of load to beprocessed.

65 After the high temperature phase of a heat sterilisation cycle, precautionsshould be taken against contamination of a sterilised load during cooling.Any cooling fluid or gas in contact with the product should be sterilisedunless it can be shown that any leaking container would not be approvedfor use.

Moist Heat

66 Both temperature and pressure should be used to monitor the process. Con-trol instrumentation should normally be independent of monitoring instru-mentation and recording charts. Where automated control and monitoringsystems are used for these applications they should be validated to ensurethat critical process requirements are met. System and cycle faults shouldbe registered by the system and observed by the operator. The reading ofthe independent temperature indicator should be routinely checked againstthe chart recorder during the sterilisation period. For sterilisers fitted witha drain at the bottom of the chamber, it may also be necessary to recordthe temperature at this position, throughout the sterilisation period. Thereshould be frequent leak tests on the chamber when a vacuum phase is partof the cycle.

67 The items to be sterilised, other than products in sealed containers, shouldbe wrapped in a material which allows removal of air and penetrationof steam but which prevents recontamination after sterilisation. All partsof the load should be in contact with the sterilising agent at the requiredtemperature for the required time.


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68 Care should be taken to ensure that steam used for sterilisation is of suit-able quality and does not contain additives at a level which could causecontamination of product or equipment.

Dry Heat

69 The process used should include air circulation within the chamber and themaintenance of a positive pressure to prevent the entry of non-sterile air.Any air admitted should be passed through a HEPA filter. Where this pro-cess is also intended to remove pyrogens, challenge tests using endotoxinsshould be used as part of the validation.

Sterilisation by Radiation

70 Radiation sterilisation is used mainly for the sterilisation of heat-sensitivematerials and products. Many medicinal products and some packagingmaterials are radiation-sensitive, so this method is permissible only whenthe absence of deleterious effects on the product has been confirmed exper-imentally. Ultraviolet irradiation is not normally an acceptable method ofsterilisation.

71 During the sterilisation procedure the radiation dose should be meas-ured. For this purpose, dosimetry indicators which are independent ofdose rate should be used, giving a quantitative measurement of the dosereceived by the product itself. Dosimeters should be inserted in the loadin sufficient number and close enough together to ensure that there isalways a dosimeter in the irradiator. Where plastic dosimeters are usedthey should be used within the time-limit of their calibration. Dosim-eter absorbances should be read within a short period after exposure toradiation.

72 Biological indicators may be used as an additional control.

73 Validation procedures should ensure that the effects of variations in densityof the packages are considered.

74 Materials handling procedures should prevent mix-up between irradiatedand non-irradiated materials. Radiation sensitive colour disks should alsobe used on each package to differentiate between packages which havebeen subjected to irradiation and those which have not.

75 The total radiation dose should be administered within a predeterminedtime span.


Sterilisation with Ethylene Oxide

76 This method should only be used when no other method is practicable.During process validation it should be shown that there is no damagingeffect on the product and that the conditions and time allowed for degassingare such as to reduce any residual gas and reaction products to definedacceptable limits for the type of product or material.

77 Direct contact between gas and microbial cells is essential; precautionsshould be taken to avoid the presence of organisms likely to be enclosedin material such as crystals or dried protein. The nature and quantity ofpackaging materials can significantly affect the process.

78 Before exposure to the gas, materials should be brought into equilibriumwith the humidity and temperature required by the process. The timerequired for this should be balanced against the opposing need to min-imise the time before sterilisation.

79 Each sterilisation cycle should be monitored with suitable biological indi-cators, using the appropriate number of test pieces distributed through-out the load. The information so obtained should form part of the batchrecord.

80 For each sterilisation cycle, records should be made of the time taken tocomplete the cycle, of the pressure, temperature and humidity within thechamber during the process and of the gas concentration and of the totalamount of gas used. The pressure and temperature should be recordedthroughout the cycle on a chart. The record(s) should form part of thebatch record.

81 After sterilisation, the load should be stored in a controlled manner underventilated conditions to allow residual gas and reaction products to reduceto the defined level. This process should be validated.

Filtration of Medicinal Products which cannot be Sterilised in theirFinal Container

82 Filtration alone is not considered sufficient when sterilisation in the finalcontainer is possible. With regard to methods currently available, steamsterilisation is to be preferred. If the product cannot be sterilised in thefinal container, solutions or liquids can be filtered through a sterile filterof nominal pore size of 0.22 micron (or less), or with at least equivalentmicro-organism retaining properties, into a previously sterilised container.Such filters can remove most bacteria and moulds, but not all viruses or


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mycoplasmas. Consideration should be given to complementing the filtra-tion process with some degree of heat treatment.

83 Due to the potential additional risks of the filtration method as comparedwith other sterilisation processes, a second filtration via a further sterilisedmicro-organism retaining filter, immediately prior to filling, may be advis-able. The final sterile filtration should be carried out as close as possible tothe filling point.

84 Fibre shedding characteristics of filters should be minimal.

85 The integrity of the sterilised filter should be verified before use and shouldbe confirmed immediately after use by an appropriate method such as abubble point, diffusive flow or pressure hold test. The time taken to filtera known volume of bulk solution and the pressure difference to be usedacross the filter should be determined during validation and any significantdifferences from this during routine manufacturing, should be noted andinvestigated. Results of these checks should be included in the batch record.The integrity of critical gas and air vent filters should be confirmed after use.The integrity of other filters should be confirmed at appropriate intervals.

86 The same filter should not be used for more than one working day unlesssuch use has been validated.

87 The filter should not affect the product by removal of ingredients from itor by release of substances into it.

Finishing of Sterile Products

88 Containers should be closed by appropriately validated methods. Contain-ers closed by fusion, e.g. glass or plastic ampoules should be subject to100% integrity testing. Samples of other containers should be checked forintegrity according to appropriate procedures.

89 Containers sealed under vacuum should be tested for maintenance of thatvacuum after an appropriate, pre-determined period.

90 Filled containers of parenteral products should be inspected individuallyfor extraneous contamination or other defects. When inspection is donevisually, it should be done under suitable and controlled conditions ofillumination and background. Operators doing the inspection should passregular eye-sight checks, with spectacles if worn, and be allowed frequentbreaks from inspection. Where other methods of inspection are used, theprocess should be validated and the performance of the equipment checkedat intervals. Results should be recorded.


Quality Control

91 The sterility test applied to the finished product should only be regardedas the last in a series of control measures by which sterility is assured. Thetest should be validated for the product(s) concerned.

92 In those cases where parametric release has been authorised, special atten-tion should be paid to the validation and the monitoring of the entiremanufacturing process.

93 Samples taken for sterility testing should be representative of the whole ofthe batch, but should in particular include samples taken from parts of thebatch considered to be most at risk of contamination, e.g.:a. for products which have been filled aseptically, samples should include

containers filled at the beginning and end of the batch and after anysignificant intervention,

b. or products which have been heat sterilised in their final containers,consideration should be given to taking samples from the potentiallycoolest part of the load.


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ANNEX 2 MANUFACTURE OF BIOLOGICAL MEDICINALPRODUCTS FOR HUMAN USE

Scope

The methods employed in the manufacture of biological medicinal productsare a critical factor in shaping the appropriate regulatory control. Biologicalmedicinal products can be defined therefore largely by reference to theirmethod of manufacture. Biological medicinal products prepared by thefollowing methods of manufacture will fall under the scope of this annex1.

Biological medicinal products manufactured by these methods include:vaccines, immunosera, antigens, hormones, cytokines, enzymes and otherproducts of fermentation (including monoclonal antibodies and productsderived from r-DNA).

(a) Microbial cultures, excluding those resulting from r-DNA techniques;(b) Microbial and cell cultures, including those resulting from recombinant

DNA or hybridoma techniques;(c) Extraction from biological tissues(d) Propagation of live agents in embryos or animals

(Not all of the aspects of this annex may necessarily apply to products inCategory a.)

Note: In drawing up this guidance, due consideration has been given tothe general requirements for manufacturing establishments and controllaboratories proposed by the WHO.

The present guidance does not lay down detailed requirements for spe-cific classes of biological products, and attention is, therefore, directed toother guidelines issued by the Committee for Proprietary Medicinal Prod-ucts (CPMP), for example the note for guidance on monoclonal antibodiesand the note for guidance on products of recombinant DNA technology(“The rules governing medicinal products in the European Community”,Volume 3).

Principle

The manufacture of biological medicinal products involves certain specificconsiderations arising from the nature of the products and the processes.The way in which biological medicinal products are produced, controlledand administered make some particular precautions necessary.

1 Biological medicinal products manufactured by these methods include: vaccines,immunosera, antigens, hormones, cytokines, enzymes and other products of fer-mentation (including monoclonal antibodies and products derived from r-DNA).


Unlike conventional medicinal products, which are reproduced usingchemical and physical techniques capable of a high degree of consistency,the production of biological medicinal products involves biological pro-cesses and materials, such as cultivation of cells or extraction of materialfrom living organisms. These biological processes may display inherentvariability, so that the range and nature of by-products are variable.Moreover, the materials used in these cultivation processes provide goodsubstrates for growth of microbial contaminants.

Control of biological medicinal products usually involves biological ana-lytical techniques which have a greater variability than physico-chemicaldeterminations. In-process controls therefore take on a great importancein the manufacture of biological medicinal products.

Personnel

1 All personnel (including those concerned with cleaning, maintenance orquality control) employed in areas where biological medicinal productsare manufactured should receive additional training specific to the prod-ucts manufactured and to their work. Personnel should be given relevantinformation and training in hygiene and microbiology.

2 Persons responsible for production and quality control should have anadequate background in relevant scientific disciplines, such as bacteriology,biology, biometry, chemistry, medicine, pharmacy, pharmacology, virology,immunology and veterinary medicine, together with sufficient practicalexperience to enable them to exercise their management function for theprocess concerned.

3 The immunological status of personnel may have to be taken into consider-ation for product safety. All personnel engaged in production, maintenance,testing and animal care (and inspectors) should be vaccinated where nec-essary with appropriate specific vaccines and have regular health checks.Apart from the obvious problem of exposure of staff to infectious agents,potent toxins or allergens, it is necessary to avoid the risk of contaminationof a production batch with infectious agents. Visitors should generally beexcluded from production areas.

4 Any changes in the immunological status of personnel which couldadversely affect the quality of the product should preclude work in the pro-duction area. Production of BCG vaccine and tuberculin products shouldbe restricted to staff who are carefully monitored by regular checks ofimmunological status or chest X-ray.

5 In the course of a working day, personnel should not pass from areas whereexposure to live organisms or animals is possible to areas where other


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products or different organisms are handled. If such passage is unavoidable,clearly defined decontamination measures, including change of clothingand shoes and, where necessary, showering should be followed by staffinvolved in any such production.

Premises and Equipment

6 The degree of environmental control of particulate and microbial contam-ination of the production premises should be adapted to the product andthe production step, bearing in mind the level of contamination of thestarting materials and the risk to the finished product.

7 The risk of cross-contamination between biological medicinal products,especially during those stages of the manufacturing process in which liveorganisms are used, may require additional precautions with respect tofacilities and equipment, such as the use of dedicated facilities and equip-ment, production on a campaign basis and the use of closed systems. Thenature of the product as well as the equipment used will determine the levelof segregation needed to avoid cross-contamination.

8 In principle, dedicated facilities should be used for the production of BCGvaccine and for the handling of live organisms used in production of tuber-culin products.

9 Dedicated facilities should be used for the handling of Bacillus anthracis,of Clostridium botulinum and of Clostridium tetani until the inactivationprocess is accomplished.

10 Production on a campaign basis may be acceptable for other spore-formingorganisms provided that the facilities are dedicated to this group of prod-ucts and not more than one product is processed at any one time.

11 Simultaneous production in the same area using closed systems of bio-fermenters may be acceptable for products such as monoclonal antibodiesand products prepared by DNA techniques.

12 Processing steps after harvesting may be carried out simultaneously in thesame production area provided that adequate precautions are taken toprevent cross-contamination. For killed vaccines and toxoids, such parallelprocessing should only be performed after inactivation of the culture orafter detoxification.

13 Positive pressure areas should be used to process sterile products but nega-tive pressure in specific areas at point of exposure of pathogens is acceptablefor containment reasons.

Where negative pressure areas or safety cabinets are used for asepticprocessing of pathogens, they should be surrounded by a positive pressuresterile zone.


14 Air filtration units should be specific to the processing area concerned andrecirculation of air should not occur from areas handling live pathogenicorganisms.

15 The layout and design of production areas and equipment should permiteffective cleaning and decontamination (e.g. by fumigation). The adequacyof cleaning and decontamination procedures should be validated.

16 Equipment used during handling of live organisms should be designed tomaintain cultures in a pure state and uncontaminated by external sourcesduring processing.

17 Pipework systems, valves and vent filters should be properly designed tofacilitate cleaning and sterilisation. The use of “clean in place” and “ster-ilise in place” systems should be encouraged. Valves on fermentation vesselsshould be completely steam sterilisable. Air vent filters should be hydro-phobic and validated for their scheduled life span.

18 Primary containment should be designed and tested to demonstrate free-dom from leakage risk.

19 Effluents which may contain pathogenic micro-organisms should be effec-tively decontaminated.

20 Due to the variability of biological products or processes, some additives oringredients have to be measured or weighed during the production process(e.g. buffers). In these cases, small stocks of these substances may be keptin the production area.

Animal Quarters and Care

21 Animals are used for the manufacture of a number of biological products,for example polio vaccine (monkeys), snake antivenoms (horses and goats),rabies vaccine (rabbits, mice and hamsters) and serum gonadotrophin(horses). In addition, animals may also be used in the quality control ofmost sera and vaccines, e.g. pertussis vaccine (mice), pyrogenicity (rabbits),BCG vaccine (guinea-pigs).

22 General requirements for animal quarters, care and quarantine are laiddown in Directive 86/609/EEC2. Quarters for animals used in production

2 Directive 2003/65/EC of the European Parliament and of the Council of 22 July2003 amending Council Directive 86/609/EEC on the approximation of laws,regulations and administrative provisions of the Member States regarding theprotection of animals used for experimental and other scientific purposes (OJ L230, 16.09.2003, p. 32–33).


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and control of biological products should be separated from productionand control areas. The health status of animals from which some startingmaterials are derived and of those used for quality control and safety test-ing should be monitored and recorded. Staff employed in such areas mustbe provided with special clothing and changing facilities. Where monkeysare used for the production or quality control of biological medicinal prod-ucts, special consideration is required as laid down in the current WHORequirements for Biological Substances N◦ 7.

Documentation

23 Specifications for biological starting materials may need additional doc-umentation on the source, origin, method of manufacture and controlsapplied, particularly microbiological controls.

24 Specifications are routinely required for intermediate and bulk biologicalmedicinal products.

Production

Starting materials

25 The source, origin and suitability of starting materials should be clearlydefined. Where the necessary tests take a long time, it may be permissibleto process starting materials before the results of the tests are available.In such cases, release of a finished product is conditional on satisfactoryresults of these tests.

26 Where sterilisation of starting materials is required, it should be carriedout where possible by heat. Where necessary, other appropriate methodsmay also be used for inactivation of biological materials (e.g. irradiation).

Seed lot and cell bank system

27 In order to prevent the unwanted drift of properties which might ensuefrom repeated subcultures or multiple generations, the production of bio-logical medicinal products obtained by microbial culture, cell culture orpropagation in embryos and animals should be based on a system of mas-ter and working seed lots and/or cell banks.

28 The number of generations (doublings, passages) between the seed lot orcell bank and the finished product should be consistent with the marketingauthorisation dossier. Scaling up of the process should not change thisfundamental relationship.


29 Seed lots and cell banks should be adequately characterised and tested forcontaminants. Their suitability for use should be further demonstratedby the consistency of the characteristics and quality of the successivebatches of product. Seed lots and cell banks should be established, storedand used in such a way as to minimise the risks of contamination oralteration.

30 Establishment of the seed lot and cell bank should be performed in a suit-ably controlled environment to protect the seed lot and the cell bank and,if applicable, the personnel handling it. During the establishment of theseed lot and cell bank, no other living or infectious material (e.g. virus, celllines or cell strains) should be handled simultaneously in the same area orby the same persons.

31 Evidence of the stability and recovery of the seeds and banks should be doc-umented. Storage containers should be hermetically sealed, clearly labelledand kept at an appropriate temperature. An inventory should be meticu-lously kept. Storage temperature should be recorded continuously for freez-ers and properly monitored for liquid nitrogen. Any deviation from setlimits and any corrective action taken should be recorded.

32 Only authorised personnel should be allowed to handle the material andthis handling should be done under the supervision of a responsible per-son. Access to stored material should be controlled. Different seed lots orcell banks should be stored in such a way to avoid confusion or cross-contamination. It is desirable to split the seed lots and cell banks and tostore the parts at different locations so as to minimise the risks of totalloss.

33 All containers of master or working cell banks and seed lots should betreated identically during storage. Once removed from storage, the con-tainers should not be returned to the stock.

Operating principles

34 The growth promoting properties of culture media should be demon-strated.

35 Addition of materials or cultures to fermenters and other vessels and thetaking of samples should be carried out under carefully controlled condi-tions to ensure that absence of contamination is maintained. Care shouldbe taken to ensure that vessels are correctly connected when addition orsampling take place.

36 Centrifugation and blending of products can lead to aerosol formation, andcontainment of such activities to prevent transfer of live micro-organismsis necessary.


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37 If possible, media should be sterilised in situ. In-line sterilising filters forroutine addition of gases, media, acids or alkalis, defoaming agents etc. tofermenters should be used where possible.

38 Careful consideration should be given to the validation of any necessaryvirus removal or inactivation undertaken (see CPMP notes for guidance).

39 In cases where a virus inactivation or removal process is performed duringmanufacture, measures should be taken to avoid the risk of recontamina-tion of treated products by non-treated products.

40 A wide variety of equipment is used for chromatography, and in generalsuch equipment should be dedicated to the purification of one productand should be sterilised or sanitised between batches. The use of the sameequipment at different stages of processing should be discouraged. Accep-tance criteria, life span and sanitation or sterilisation method of columnsshould be defined.

Quality Control

41 In-process controls play a specially important role in ensuring the consis-tency of the quality of biological medicinal products. Those controls, whichare crucial for quality (e.g. virus removal) but which cannot be carried outon the finished product, should be performed at an appropriate stage ofproduction.

42 It may be necessary to retain samples of intermediate products in sufficientquantities and under appropriate storage conditions to allow the repetitionor confirmation of a batch control.

43 Continuous monitoring of certain production processes is necessary, forexample fermentation. Such data should form part of the batch record.

44 Where continuous culture is used, special consideration should be givento the quality control requirements arising from this type of productionmethod.


ANNEX 3 MANUFACTURE OF RADIOPHARMACEUTICALS

Principle

The manufacturing and handling of radiopharmaceuticals is potentiallyhazardous. The level of risk depends in particular upon the types of radi-ation emitted and the half-lives of the radioactive isotopes. Particular atten-tion must be paid to the prevention of cross-contamination, to the retentionof radionuclide contaminants, and to waste disposal.

Special consideration may be necessary with reference to the small batchsizes made frequently for many radiopharmaceuticals. Due to their shorthalf-life, some radiopharmaceuticals are released before completion of cer-tain Quality Control tests. In this case, the continuous assessment of theeffectiveness of the Quality Assurance system becomes very important.

Note: Manufacture must comply with the requirements of EURATOMDirectives laying down the basic standards for the health protection of thegeneral public and workers against the dangers of ionising radiation, aswell as complying with other relevant national requirements.

Personnel

1 All personnel (including those concerned with cleaning and maintenance)employed in areas where radioactive products are manufactured shouldreceive additional training specific to this class of products. In particular,they should be given detailed information and appropriate training onradiation protection.


2 Radioactive products should be stored, processed, packaged and controlledin dedicated and self-contained facilities. The equipment used for manufac-turing operations should be reserved exclusively for radiopharmaceuticals.

3 In order to contain the radioactive particles, it may be necessary for the airpressure to be lower where products are exposed than in surrounding areas.However, it is still necessary to protect the product from environmentalcontamination.

4 For sterile products the working zone where products or containers may beexposed should comply with the environmental requirements described inthe Supplement on Sterile Products. This may be achieved by the provisionwithin the work station of a laminar flow of HEPA-filtered air and by fitting


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air-locks to entry ports. Total containment work stations may provide theserequirements. They should be in an environment conforming to at leastgrade D.

5 Air extracted from areas where radioactive products are handled shouldnot be re-circulated; air outlets should be designed to avoid possibleenvironmental contamination by radioactive particles and gases.

There should be a system to prevent air entering the clean area throughextract ducts e.g. when the extract fan is not operating.

Production

6 Production of different radioactive products in the same work stationsand at the same time should be avoided in order to minimise the risk ofcross-contamination or mix-up.

7 Process validation, in-process controls and monitoring of process param-eters and environment, assume particular importance in cases where it isnecessary to take the decision to release or reject a batch or a productbefore all tests are completed.

Quality Control

8 When products have to be dispatched before all tests are completed, thisdoes not obviate the need for a formal recorded decision to be taken by theQualified Person on the conformity of the batch. In this case there shouldbe a written procedure detailing all production and Quality Control datawhich should be considered before the batch is dispatched. A procedureshould also describe the measures to be taken by the Qualified Person ifunsatisfactory test results are obtained after dispatch.

9 Unless otherwise specified in the marketing authorisation, reference sam-ples of every batch should be retained.

Distribution and Recalls

10 Detailed distribution records should be maintained and there should beprocedures which describe the measures to be taken for stopping the useof defective radiopharmaceuticals. Recall operations should be shown tobe operable within a very short time.


ANNEX 4 MANUFACTURE OF VETERINARY MEDICINALPRODUCTS OTHER THAN IMMUNOLOGICAL VETERINARYMEDICINAL PRODUCTS

Note: This annex applies to all veterinary medicinal products fallingwithin the scope of Directive 2001/82/EC other than immunological vet-erinary medicinal products, which are the subject of a separate annex.

Manufacture of Premixes for Medicated Feedingstuffs

For the purposes of these paragraphs,

� a medicated feedingstuff is any mixture of a veterinary medicinal productor products and feed or feeds which is ready prepared for marketing andintended to be fed to animals without further processing because of itscurative or preventative properties or other properties as a medicinalproduct covered by Article 1(2) of Directive 2001/82/EC;� a pre-mix for medicated feedingstuffs is any veterinary medicinal prod-uct prepared in advance with a view to the subsequent manufacture ofmedicated feedingstuffs.

1 The manufacture of premixes for medicated feedingstuffs requires the useof large quantities of vegetable matter which is likely to attract insects androdents. Premises should be designed, equipped and operated to minimisethis risk (point 3.4) and should also be subject to a regular pest controlprogramme.

2 Because of the large volume of dust generated during the production ofbulk material for premixes, specific attention should be given to the need toavoid cross-contamination and facilitate cleaning (point 3.14), for examplethrough the installation of sealed transport systems and dust extraction,whenever possible. The installation of such systems does not, however,eliminate the need for regular cleaning of production areas.

3 Parts of the process likely to have a significant adverse influence on thestability of the active ingredient(s) (e.g. use of steam in pellet manufacture)should be carried out in an uniform manner from batch to batch.

4 Consideration should be given to undertake the manufacture of premixesin dedicated areas which, if at all possible, do not form part of a mainmanufacturing plant. Alternatively, such dedicated areas should be sur-rounded by a buffer zone in order to minimise the risk of contaminationof other manufacturing areas.


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Manufacture of Ectoparasiticides

5 In derogation from point 3.6, ectoparasiticides for external application toanimals, which are veterinary medicinal products, and subject to marketingauthorisation, may be produced and filled on a campaign basis in pesticidespecific areas. However other categories of veterinary medicinal productsshould not be produced in such areas.

6 Adequate validated cleaning procedures should be employed to preventcross-contamination, and steps should be taken to ensure the securestorage of the veterinary medicinal product in accordance with theguide.

Manufacture of Veterinary Medicinal Products Containing Penicillins

7 The use of penicillins in veterinary medicine does not present the samerisks of hypersensitivity in animals as in humans. Although incidents ofhypersensitivity have been recorded in horses and dogs, there are othermaterials which are toxic to certain species, e.g. the ionophore anti-biotics in horses. Although desirable, the requirements that such productsbe manufactured in dedicated, self-contained facilities (point 3.6) may bedispensed with in the case of facilities dedicated to the manufacture of vet-erinary medicinal products only. However, all necessary measures shouldbe taken to avoid cross-contamination and any risk to operator safety inaccordance with the guide. In such circumstances, penicillin-containingproducts should be manufactured on a campaign basis and shouldbe followed by appropriate, validated decontamination and cleaningprocedures.

Retention of Samples (point 1.4 viii and point 6.14)

8 It is recognised that because of the large volume of certain veterinary medi-cinal products in their final packaging, in particular premixes, it may notbe feasible for manufacturers to retain samples from each batch in its finalpackaging. However, manufacturers should ensure that sufficient represen-tative samples of each batch are retained and stored in accordance with theguide.

9 In all cases, the container used for storage should be composed of the samematerial as the market primary container in which the product is marketed.


Sterile Veterinary Medicinal Products

10 Where this has been accepted by the competent authorities, terminallysterilised veterinary medicinal products may be manufactured in a cleanarea of a lower grade than the grade required in the annex on “Sterilepreparations,” but at least in a grade D environment.


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ANNEX 5 MANUFACTURE OF IMMUNOLOGICAL VETERINARYMEDICINAL PRODUCTS

Principle

The manufacture of immunological veterinary medicinal products has spe-cial characteristics which should be taken into consideration when imple-menting and assessing the quality assurance system.

Due to the large number of animal species and related pathogenic agents,the variety of products manufactured is very wide and the volume ofmanufacture is often low; hence, work on a campaign basis is common.Moreover, because of the very nature of this manufacture (cultivation steps,lack of terminal sterilisation, etc.), the products must be particularly well-protected against contamination and cross-contamination. The environ-ment also must be protected especially when the manufacture involves theuse of pathogenic or exotic biological agents and the worker must be par-ticularly well-protected when the manufacture involves the use of biologi-cal agents pathogenic to man.

These factors, together with the inherent variability of immunologicalproducts and the relative inefficiency in particular of final product qual-ity control tests in providing adequate information about products, meansthat the role of the quality assurance system is of the utmost importance.The need to maintain control over all of the following aspects of GMP, aswell as those outlined in this Guide, cannot be overemphasised. In particu-lar, it is important that the data generated by the monitoring of the variousaspects of GMP (equipment, premises, product, etc.) are rigorously assessedand informed decisions, leading to appropriate action, are made andrecorded.

Personnel

1 All personnel (including those concerned with cleaning and maintenance)employed in areas where immunological products are manufactured shouldbe given training in and information on hygiene and microbiology. Theyshould receive additional training specific to the products with which theywork.

2 Responsible personnel should be formally trained in some or all of thefollowing fields: bacteriology, biology, biometry, chemistry, immunology,medicine, parasitology, pharmacy, pharmacology, virology and veterinarymedicine and should also have an adequate knowledge of environmentalprotection measures.


3 Personnel should be protected against possible infection with the biolog-ical agents used in manufacture. In the case of biological agents knownto cause disease in humans, adequate measures should be taken to pre-vent infection of personnel working with the agent or with experimentalanimals.

Where relevant, the personnel should be vaccinated and subject tomedical examination.

4 Adequate measures should be taken to prevent biological agents beingtaken outside the manufacturing plant by personnel acting as a carrier.Dependent on the type of biological agent, such measures may includecomplete change of clothes and compulsory showering before leaving theproduction area.

5 For immunological products, the risk of contamination or cross-contamination by personnel is particularly important.

Prevention of contamination by personnel should be achieved by a setof measures and procedures to ensure that appropriate protective clothingis used during the different stages of the production process.

Prevention of cross-contamination by personnel involved in productionshould be achieved by a set of measures and procedures to ensure that theydo not pass from one area to another unless they have taken appropriatemeasures to eliminate the risk of contamination. In the course of a workingday, personnel should not pass from areas where contamination with livemicro-organisms is likely or where animals are housed to premises whereother products or organisms are handled. If such passage is unavoidable,clearly defined decontamination procedures, including change of clothingand shoes, and, where necessary, showering, should be followed by staffinvolved in any such production.

Personnel entering a contained area where organisms had not been han-dled in open circuit operations in the previous twelve hours to check oncultures in sealed, surface decontaminated flasks would not be regardedas being at risk of contamination, unless the organism involved was anexotic.

Premises

6 Premises should be designed in such a way as to control both the risk tothe product and to the environment.

This can be achieved by the use of containment, clean, clean/containedor controlled areas.

7 Live biological agents should be handled in contained areas. The level ofcontainment should depend on the pathogenicity of the micro-organism


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and whether it has been classified as exotic. (Other relevant legislation,such as Directives 90/219/EEC1 and 90/220/EEC,2 also applies).

8 Inactivated biological agents should be handled in clean areas. Clean areasshould also be used when handling non-infected cells isolated from multi-cellular organisms and, in some cases, filtration-sterilised media.

9 Open circuit operations involving products or components not subse-quently sterilised should be carried out within a laminar air flow workstation (grade A) in a grade B area.

10 Other operations where live biological agents are handled (quality control,research and diagnostic services, etc.) should be appropriately containedand separated if production operations are carried out in the same build-ing. The level of containment should depend on the pathogenicity of thebiological agent and whether they have been classified as exotic. When-ever diagnostic activities are carried out, there is the risk of introducinghighly pathogenic organisms. Therefore, the level of containment shouldbe adequate to cope with all such risks. Containment may also be requiredif quality control or other activities are carried out in buildings in closeproximity to those used for production.

11 Containment premises should be easily disinfected and should have thefollowing characteristics:

(a) the absence of direct venting to the outside;(b) a ventilation with air at negative pressure. Air should be extracted

through HEPA filters and not be re circulated except to the same area,and provided further HEPA filtration is used (normally this conditionwould be met by routing the re circulated air through the normal sup-ply HEPAs for that area). However, recycling of air between areas maybe permissible provided that it passes through two exhaust HEPAs, thefirst of which is continuously monitored for integrity, and there areadequate measures for safe venting of exhaust air should this filter fail;

(c) air from manufacturing areas used for the handling of exotic organismsshould be vented through 2 sets of HEPA filters in series, and that fromproduction areas not re-circulated;

1 Council Directive 98/81/EC of 26 October 1998 amending Directive 90/219/EECon the contained use of genetically modified micro-organisms (OJ L 330,05.12.1998, p. 13–31).

2 Directive 2001/18/EC of the European Parliament and of the Council of 12March 2001 on the deliberate release into the environment of genetically mod-ified organisms and repealing Council Directive 90/220/EEC – CommissionDeclaration (OJ L 106, 17.04.2001, p. 01–39).


(d) a system for the collection and disinfection of liquid effluents includ-ing contaminated condensate from sterilizers, biogenerators, etc. Solidwastes, including animal carcasses, should be disinfected, sterilized orincinerated as appropriate. Contaminated filters should be removedusing a safe method;

(e) changing rooms designed and used as air locks, and equipped withwashing and showering facilities if appropriate. Air pressure differen-tials should be such that there is no flow of air between the work areaand the external environment or risk of contamination of outer clothingworn outside the area;

(f) an air lock system for the passage of equipment, which is constructed sothat there is no flow of contaminated air between the work area and theexternal environment or risk of contamination of equipment within thelock. The air lock should be of a size which enables the effective surfacedecontamination of materials being passed through it. Considerationshould be given to having a timing device on the door interlock to allowsufficient time for the decontamination process to be effective.

(g) in many instances, a barrier double-door autoclave for the secureremoval of waste materials and introduction of sterile items.

12 Equipment passes and changing rooms should have an interlock mecha-nism or other appropriate system to prevent the opening of more than onedoor at a time. Changing rooms should be supplied with air filtered to thesame standard as that for the work area, and equipped with air extractionfacilities to produce an adequate air circulation independent of that of thework area. Equipment passes should normally be ventilated in the sameway, but unventilated passes, or those equipped with supply air only, maybe acceptable.

13 Production operations such as cell maintenance, media preparation, virusculture, etc. likely to cause contamination should be performed in separateareas. Animals and animal products should be handled with appropriateprecautions.

14 Production areas where biological agents particularly resistant to disin-fection (e.g. spore-forming bacteria) are handled should be separated anddedicated to that particular purpose until the biological agents have beeninactivated.

15 With the exception of blending and subsequent filling operations, onebiological agent only should be handled at a time within an area.

16 Production areas should be designed to permit disinfection between cam-paigns, using validated methods.

17 Production of biological agents may take place in controlled areas pro-vided it is carried out in totally enclosed and heat sterilised equipment,


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all connections being also heat sterilised after making and before break-ing. It may be acceptable for connections to be made under local lam-inar air flow provided these are few in number and proper aseptic tech-niques are used and there is no risk of leakage. The sterilisation parametersused before breaking the connections must be validated for the organ-isms being used. Different products may be placed in different biogener-ators, within the same area, provided that there is no risk of accidentalcross-contamination. However, organisms generally subject to specialrequirements for containment should be in areas dedicated to suchproducts.

18 Animal houses where animals intended or used for production are accom-modated, should be provided with the appropriate containment and/orclean area measures, and should be separate from other animal accommo-dation.

Animal houses where animals used for quality control, involving the useof pathogenic biological agents, are accommodated, should be adequatelycontained.

19 Access to manufacturing areas should be restricted to authorised personnel.Clear and concise written procedures should be posted as appropriate.

20 Documentation relating to the premises should be readily available in aplant master file.

The manufacturing site and buildings should be described in sufficientdetail (by means of plans and written explanations) so that the designationand conditions of use of all the rooms are correctly identified as well asthe biological agents which are handled in them. The flow of people andproduct should also be clearly marked.

The animal species accommodated in the animal houses or otherwise onthe site should be identified.

The activities carried out in the vicinity of the site should also be indi-cated. Plans of contained and/or clean area premises, should describe theventilation system indicating inlets and outlets, filters and their specifica-tions, the number of air changes per hour, and pressure gradients. Theyshould indicate which pressure gradients are monitored by pressure indi-cator.

Equipment

21 The equipment used should be designed and constructed so that it meetsthe particular requirements for the manufacture of each product.

Before being put into operation the equipment should be qualified andvalidated and subsequently be regularly maintained and validated.


22 Where appropriate, the equipment should ensure satisfactory primary con-tainment of the biological agents.

Where appropriate, the equipment should be designed and constructedas to allow easy and effective decontamination and/or sterilisation.

23 Closed equipment used for the primary containment of the biologicalagents should be designed and constructed as to prevent any leakage orthe formation of droplets and aerosols.

Inlets and outlets for gases should be protected so as to achieve adequatecontainment e.g. by the use of sterilising hydrophobic filters.

The introduction or removal of material should take place using asterilisable closed system, or possibly in an appropriate laminar airflow.

24 Equipment where necessary should be properly sterilised before use, prefer-ably by pressurised dry steam. Other methods can be accepted if steamsterilisation cannot be used because of the nature of the equipment. It isimportant not to overlook such individual items as bench centrifuges andwater baths.

Equipment used for purification, separation or concentration shouldbe sterilised or disinfected at least between use for different products.The effect of the sterilisation methods on the effectiveness and validityof the equipment should be studied in order to determine the life span ofthe equipment.

All sterilisation procedures should be validated.

25 Equipment should be designed so as to prevent any mix-up between dif-ferent organisms or products. Pipes, valves and filters should be identifiedas to their function.

Separate incubators should be used for infected and non infected contain-ers and also generally for different organisms or cells. Incubators containingmore than one organism or cell type will only be acceptable if adequatesteps are taken to seal, surface decontaminate and segregate the contain-ers. Culture vessels, etc. should be individually labelled. The cleaning anddisinfection of the items can be particularly difficult and should receivespecial attention.

Equipment used for the storage of biological agents or products shouldbe designed and used in such a manner as to prevent any possible mix-up.All stored items should be clearly and unambiguously labelled and in leak-proof containers. Items such as cells and organisms seed stock should bestored in dedicated equipment.

26 Relevant equipment, such as that requiring temperature control, should befitted with recording and/or alarm systems.

To avoid breakdowns, a system of preventive maintenance, together withtrend analysis of recorded data, should be implemented.


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27 The loading of freeze dryers requires an appropriate clean/containedarea.

Unloading freeze dryers contaminates the immediate environment.Therefore, for single-ended freeze dryers, the clean room should be decon-taminated before a further manufacturing batch is introduced into thearea, unless this contains the same organisms, and double door freezedryers should be sterilised after each cycle unless opened in a cleanarea.

Sterilisation of freeze dryers should be done in accordance with item 24.In case of campaign working, they should at least be sterilised after eachcampaign.

Animals and Animal Houses

28 General requirements for animal quarters, care and quarantine are laiddown in Directive 86/609/EEC3.

29 Animal houses should be separated from the other production premisesand suitably designed.

30 The sanitary status of the animals used for production should be defined,monitored, and recorded. Some animals should be handled as defined inspecific monographs (e.g. Specific Pathogen Free flocks).

31 Animals, biological agents, and tests carried out should be the subject of anidentification system so as to prevent any risk of confusion and to controlall possible hazards.

Disinfection–Waste Disposal

32 Disinfection and/or wastes and effluents disposal may be particularlyimportant in the case of manufacture of immunological products. Care-ful consideration should therefore be given to procedures and equipmentaiming at avoiding environmental contamination as well as to their vali-dation or qualification.

3 Directive 2003/65/EC of the European Parliament and of the Council of 22 July2003 amending Council Directive 86/609/EEC on the approximation of laws,regulations and administrative provisions of the Member States regarding theprotection of animals used for experimental and other scientific purposes (OJ L230 , 16.09.2003, p. 32–33).


Production

33 Because of the wide variety of products, the frequently large number ofstages involved in the manufacture of immunological veterinary medicinalproducts and the nature of the biological processes, careful attention mustbe paid to adherence to validated operating procedures, to the constantmonitoring of production at all stages and to in-process controls.

Additionally, special consideration should be given to starting materials,media and the use of a seed lot system.

Starting Materials

34 The suitability of starting materials should be clearly defined in writtenspecifications. These should include details of the supplier, the method ofmanufacture, the geographical origin and the animal species from whichthe materials are derived. The controls to be applied to starting materialsmust be included. Microbiological controls are particularly important.

35 The results of tests on starting materials must comply with the specifica-tions. Where the tests take a long time (e.g. eggs from SPF flocks) it maybe necessary to process starting materials before the results of analyticalcontrols are available. In such cases, the release of a finished product isconditional upon satisfactory results of the tests on starting materials.

36 Special attention should be paid to a knowledge of the supplier’s qualityassurance system in assessing the suitability of a source and the extent ofquality control testing required.

37 Where possible, heat is the preferred method for sterilising starting ma-terials. If necessary, other validated methods, such as irradiation, may beused.

Media

38 The ability of media to support the desired growth should be properlyvalidated in advance.

39 Media should preferably be sterilised in situ or in line. Heat is the preferredmethod. Gases, media, acids, alkalis, de-foaming agents and other materialsintroduced into sterile biogenerators should themselves be sterile.

Seed lot and cell bank system

40 In order to prevent the unwanted drift of properties which might ensuefrom repeated subcultures or multiple generations, the production of


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immunological veterinary medicinal products obtained by microbial, cellor tissue culture, or propagation in embryos and animals, should be basedon a system of seed lots or cell banks.

41 The number of generations (doublings, passages) between the seed lot orcell bank and the finished product should be consistent with the dossier ofauthorisation for marketing.

42 Seed lots and cell banks should be adequately characterised and tested forcontaminants. Acceptance criteria for new seed lots should be established.Seed lots and cell banks shall be established, stored and used in such a wayas to minimise the risks of contamination, or any alteration. During theestablishment of the seed lot and cell bank, no other living or infectiousmaterial (e.g. virus or cell lines) shall be handled simultaneously in the samearea or by the same person.

43 Establishment of the seed lot and cell bank should be performed in a suit-able environment to protect the seed lot and the cell bank and, if applicable,the personnel handling it and the external environment.

44 The origin, form and storage conditions of seed material should bedescribed in full. Evidence of the stability and recovery of the seeds andcells should be provided. Storage containers should be hermetically sealed,clearly labelled and stored at an appropriate temperature. Storage condi-tions shall be properly monitored. An inventory should be kept and eachcontainer accounted for.

45 Only authorised personnel should be allowed to handle the material andthis handling should be done under the supervision of a responsible person.Different seed lots or cell banks shall be stored in such a way to avoidconfusion or cross-contamination errors. It is desirable to split the seedlots and cell banks and to store the parts at different locations so as tominimise the risk of total loss.

Operating principles

46 The formation of droplets and the production of foam should be avoided orminimised during manufacturing processes. Centrifugation and blendingprocedures which can lead to droplet formation should be carried out inappropriate contained or clean/contained areas to prevent transfer of liveorganisms.

47 Accidental spillages, especially of live organisms, must be dealt with quicklyand safely. Validated decontamination measures should be available foreach organism. Where different strains of single bacteria species or verysimilar viruses are involved, the process need be validated against only one


of them, unless there is reason to believe that they may vary significantlyin their resistance to the agent(s) involved.

48 Operations involving the transfer of materials such as sterile media, culturesor product should be carried out in pre-sterilised closed systems whereverpossible. Where this is not possible, transfer operations must be protectedby laminar airflow work stations.

49 Addition of media or cultures to biogenerators and other vessels should becarried out under carefully controlled conditions to ensure that contam-ination is not introduced. Care must be taken to ensure that vessels arecorrectly connected when addition of cultures takes place.

50 Where necessary, for instance when two or more fermenters are within asingle area, sampling and addition ports, and connectors (after connection,before the flow of product, and again before disconnection) should besterilised with steam. In other circumstances, chemical disinfection of portsand laminar air flow protection of connections may be acceptable.

51 Equipment, glassware, the external surfaces of product containers andother such materials must be disinfected before transfer from a containedarea using a validated method (see item 47 above). Batch documentationcan be a particular problem. Only the absolute minimum required to allowoperations to GMP standards should enter and leave the area. If obviouslycontaminated, such as by spills or aerosols, or if the organism involved isan exotic, the paperwork must be adequately disinfected through an equip-ment pass, or the information transferred out by such means as photocopyor fax.

52 Liquid or solid wastes such as the debris after harvesting eggs, disposableculture bottles, unwanted cultures or biological agents, are best sterilisedor disinfected before transfer from a contained area. However, alternativessuch as sealed containers or piping may be appropriate in some cases.

53 Articles and materials, including documentation, entering a productionroom should be carefully controlled to ensure that only articles and ma-terials concerned with production are introduced. There should be a systemwhich ensures that articles and materials entering a room are reconciledwith those leaving so that their accumulation within the room does notoccur.

54 Heat stable articles and materials entering a clean area or clean/containedarea should do so through a double-ended autoclave or oven. Heat labilearticles and materials should enter through an air-lock with interlockeddoors where they are disinfected. Sterilisation of articles and materialselsewhere is acceptable provided that they are double wrapped and enterthrough an airlock with the appropriate precautions.


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55 Precautions must be taken to avoid contamination or confusion dur-ing incubation. There should be a cleaning and disinfection procedurefor incubators. Containers in incubators should be carefully and clearlylabelled.

56 With the exception of blending and subsequent filling operations (or whentotally enclosed systems are used) only one live biological agent may behandled within a production room at any given time. Production roomsmust be effectively disinfected between the handling of different live bio-logical agents.

57 Products should be inactivated by the addition of inactivant accompaniedby sufficient agitation. The mixture should then be transferred to a secondsterile vessel, unless the container is of such a size and shape as to beeasily inverted and shaken so as to wet all internal surfaces with the finalculture/inactivant mixture.

58 Vessels containing inactivated products should not be opened or sampledin areas containing live biological agents. All subsequent processing ofinactivated products should take place in clean areas grade A-B or enclosedequipment dedicated to inactivated products.

59 Careful consideration should be given to the validation of methods forsterilisation, disinfection, virus removal and inactivation.

60 Filling should be carried out as soon as possible following pro-duction. Containers of bulk product prior to filling should besealed, appropriately labelled and stored under specified conditions oftemperature.

61 There should be a system to assure the integrity and closure of containersafter filling.

62 The capping of vials containing live biological agents must be performedin such a way that ensures that contamination of other products or escapeof the live agents into other areas or the external environment does notoccur.

63 For various reasons there may be a delay between the filling of final con-tainers and their labelling and packaging. Procedures should be specifiedfor the storage of unlabelled containers in order to prevent confusion and toensure satisfactory storage conditions. Special attention should be paid tothe storage of heat labile or photosensitive products. Storage temperaturesshould be specified.

64 For each stage of production, the yield of product should be reconciledwith that expected from that process. Any significant discrepancies shouldbe investigated.


Quality control

65 In-process controls play a specially important role in ensuring the consis-tency of the quality of biological medicinal products. Those controls whichare crucial for the quality (e.g. virus removal) but which cannot be carriedout on the finished product, should be performed at an appropriate stageof production.

66 It may be necessary to retain samples of intermediate products in sufficientamount and under appropriate storage conditions to allow repetition orconfirmation of a batch control.

67 There may be a requirement for the continuous monitoring of data during aproduction process, for example monitoring of physical parameters duringfermentation.

68 Continuous culture of biological products is a common practice and specialconsideration needs to be given to the quality control requirements arisingfrom this type of production method.


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ANNEX 6 MANUFACTURE OF MEDICINAL GASES

1 Principle

This annex deals with industrial manufacturing of medicinal gases, which isa specialised industrial process not normally undertaken by pharmaceuticalcompanies. It does not cover manufacturing and handling of medicinalgases in hospitals, which will be subject to national legislation. Howeverrelevant parts of this annex may be used as a basis for such activities.

The manufacture of medicinal gases is generally carried out in closedequipment. Consequently, environmental contamination of the product isminimal. However, there is a risk of cross-contamination with other gases.

Manufacture of medicinal gases should comply with the basic require-ments of GMP, with applicable annexes, Pharmacopoeial standards andthe following detailed guidelines.

2 Personnel

2.1 The qualified person responsible for release of medicinal gases should havea thorough knowledge of the production and control of medicinal gases.

2.2 All personnel involved in the manufacture of medicinal gases should under-stand the GMP requirements relevant to medicinal gases and should beaware of the critically important aspects and potential hazards for patientsfrom products in the form of medicinal gases.

3 Premises and Equipment

3.1 Premises

3.1.1 Medicinal gases should be filled in a separate area from non-medicinalgases and there should be no exchange of containers between these areas.In exceptional cases, the principal of campaign filling in the same areacan be accepted provided that specific precautions are taken and necessaryvalidation is done.

3.1.2 Premises should provide sufficient space for manufacturing, testing andstorage operations to avoid the risk of mix-up. Premises should be cleanand tidy to encourage orderly working and adequate storage.

3.1.3 Filling areas should be of sufficient size and have an orderly layout toprovide:

(a) separate marked areas for different gases;


(b) clear identification and segregation of empty cylinders and cylinders atvarious stages of processing (e.g. “awaiting filling”, “filled”, “quaran-tine”, “approved”, “rejected”).

The method used to achieve these various levels of segregation willdepend on the nature, extent and complexity of the overall operation,but marked-out floor areas, partitions, barriers and signs could be used orother appropriate means.

3.2 Equipment

3.2.1 All equipment for manufacture and analyses should be qualified and cali-brated regularly as appropriate.

3.2.2 It is necessary to ensure that the correct gas is put into the correct con-tainer. Except for validated automated filling processes there should be nointerconnections between pipelines carrying different gases. The manifoldsshould be equipped with fill connections that correspond only to the valvefor that particular gas or particular mixture of gases so that only the cor-rect containers can be attached to the manifold. (The use of manifold andcontainer valve connections may be subject to international or nationalstandards.)

3.2.3 Repair and maintenance operations should not affect the quality of themedicinal gases.

3.2.4 Filling of non-medicinal gases should be avoided in areas and with equip-ment destined for the production of medicinal gases. Exceptions can beacceptable if the quality of the gas used for non-medicinal purposes is atleast equal to the quality of the medicinal gas and GMP-standards aremaintained. There should be a validated method of backflow preventionin the line supplying the filling area for non-medicinal gases to preventcontamination of the medicinal gas.

3.2.5 Storage tanks and mobile delivery tanks should be dedicated to one gasand a well-defined quality of this gas. However liquefied medicinal gasesmay be stored or transported in the same tanks as the same non-medicinalgas provided that the quality of the latter is at least equal to the quality ofthe medicinal gas.

4 Documentation

4.1 Data included in the records for each batch of cylinders filled must ensurethat each filled cylinder is traceable to significant aspects of the relevantfilling operations. As appropriate, the following should be entered:


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� the name of the product;� the date and the time of the filling operations;� a reference to the filling station used;� equipment used;� name and reference to the specification of the gas or each gas in a

mixture;� pre filling operations performed (see point 5.3.5);� the quantity and size of cylinders before and after filling;� the name of the person carrying out the filling operation;� the initials of the operators for each significant step (line clearance,

receipt of cylinders, emptying of cylinders etc.);� key parameters that are needed to ensure correct fill at standard condi-

tions;� the results of quality control tests and where test equipment is calibrated

before each test, the reference gas specification and calibration checkresults;

� results of appropriate checks to ensure the containers have beenfilled;

� a sample of the batch code label;� details of any problems or unusual events, and signed authorisation for

any deviation from filling instructions;� to indicate agreement, the date and signature of the supervisor respon-

sible for the filling operation.

5 Production

5.1 All critical steps in the different manufacturing processes should be subjectto validation.

5.2 Bulk Production

5.2.1 Bulk gases intended for medicinal use could be prepared by chemical syn-thesis or obtained from natural resources followed by purification steps ifnecessary (as for example in an air separation plant). These gases could beregarded as Active Pharmaceutical Ingredients (API) or as bulk pharma-ceutical products as decided by the national competent authority.

5.2.2 Documentation should be available specifying the purity, other compo-nents and possible impurities that may be present in the source gas andat purification steps, as applicable. Flow charts of each different processshould be available.

5.2.3 All separation and purification steps should be designed to operate atoptimal effectiveness. For example, impurities that may adversely affecta purification step should be removed before this step is reached.


5.2.4 Separation and purification steps should be validated for effectiveness andmonitored according to the results of the validation. Where necessary,in-process controls should include continuous analysis to monitor theprocess. Maintenance and replacement of expendable equipment compo-nents, e.g. purification filters, should be based on the results of monitoringand validation.

5.2.5 If applicable, limits for process temperatures should be documented andin-process monitoring should include temperature measurement.

5.2.6 Computer systems used in controlling or monitoring processes should bevalidated.

5.2.7 For continuous processes, a definition of a batch should be documentedand related to the analysis of the bulk gas.

5.2.8 Gas production should be continuously monitored for quality andimpurities.

5.2.9 Water used for cooling during compression of air should be monitored formicrobiological quality when in contact with the medicinal gas.

5.2.10 All the transfer operations, including controls before transfers, of liquefiedgases from primary storage should be in accordance with written proce-dures designed to avoid any contamination. The transfer line should beequipped with a non-return valve or other suitable alternative. Particularattention should be paid to purge the flexible connections and to couplinghoses and connectors.

5.2.11 Deliveries of gas may be added to bulk storage tanks containing the samegas from previous deliveries. The results of a sample must show that thequality of the delivered gas is acceptable. Such a sample could be takenfrom:

� the delivered gas before the delivery is added; or� from the bulk tank after adding and mixing

5.2.12 Bulk gases intended for medicinal use should be defined as a batch,controlled in accordance with relevant Pharmacopoeial monographs andreleased for filling.

5.3 Filling and labelling

5.3.1 For filling of medicinal gases the batch should be defined.

5.3.2 Containers for medicinal gases should conform to appropriate technicalspecifications. Valve outlets should be equipped with tamper-evident seals


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after filling. Cylinders should preferably have minimum retention valves inorder to get adequate protection against contamination.

5.3.3 The medicinal gases filling manifold as well as the cylinders should bededicated to a single medicinal gas or to a given mixture of medicinalgases (see also point 3.2.2). There should be a system in place ensuringtraceability of cylinders and valves.

5.3.4 Cleaning and purging of filling equipment and pipelines should be car-ried out according to written procedures. This is especially important aftermaintenance or breaches of system integrity. Checks for the absence of con-taminants should be carried out before the line is released for use. Recordsshould be maintained.

5.3.5 Cylinders should be subject to an internal visual inspection when:

� they are new� in connection with any hydrostatic pressure test or equivalent test

After fitting of the valve, the valve should be maintained in a closed positionto prevent any contamination from entering the cylinder.

5.3.6 Checks to be performed before filling should include:

� a check to determine the residual pressure (> 3 to 5 bar) to ensure thatthe cylinder is not emptied;

� cylinders with no residual pressure should be put aside for additionalmeasures to make sure they are not contaminated with water or othercontaminants. These could include cleaning with validated methods orvisual inspection as justified;

� assuring that all batch labels and other labels if damaged have beenremoved;

� visual external inspection of each valve and container for dents, arcburns, debris, other damage and contamination with oil or grease; cylin-ders should be cleaned, tested and maintained in an appropriate manner;

� a check of each cylinder or cryogenic vessel valve connection to deter-mine that it is the proper type for the particular medicinal gas involved;

� a check of the cylinder “test code date” to determine that the hydrostaticpressure test or equivalent test has been conducted and still is valid asrequired by national or international guidelines;

� a check to determine that each container is colour-coded according tothe relevant standard

5.3.7 Cylinders which have been returned for refilling should be prepared withgreat care in order to minimise risks for contamination. For compressedgases a maximum theoretical impurity of 500 ppm v/v should be obtainedfor a filling pressure of 200 bar (and equivalent for other filling pressures).Cylinders could be prepared as follows:


� any gas remaining in the cylinders should be removed by evacuating thecontainer [at least to a remaining absolute pressure of 150 millibar]or

� by blowing down each container, followed by purging using validatedmethods (partial pressurisation at least to 7 bar and then blowing down).

For cylinders equipped with residual (positive) pressure valves, one evacu-ation under vacuum at 150 millibar is sufficient if the pressure is positive.As an alternative, full analysis of the remaining gas should be carried outfor each individual container.

5.3.8 There should be appropriate checks to ensure that containers have beenfilled. An indication that it is filling properly could be to ensure that theexterior of the cylinder is warm by touching it lightly during filling.

5.3.9 Each cylinder should be labelled and colour-coded. The batch numberand/or filling date and expiry date may be on a separate label.

6 Quality Control

6.1 Water used for hydrostatic pressure testing should be at least of drinkingwater quality and monitored routinely for microbiological contamination.

6.2 Each medicinal gas should be tested and released according to its specifi-cations. In addition, each medicinal gas should be tested to full relevantpharmacopoeial requirements at sufficient frequency to assure ongoingcompliance.

6.3 The bulk gas supply should be released for filling (see point 5.2.12).

6.4 In the case of a single medicinal gas filled via a multi-cylinder manifold, atleast one cylinder of product from each manifold filling should be testedfor identity, assay and if necessary water content each time the cylindersare changed on the manifold.

6.5 In the case of a single medicinal gas filled into cylinders one at a time byindividual filling operations, at least one cylinder of each uninterruptedfilling cycle should be tested for identity and assay. An example of anuninterrupted filling operation cycle is one shift’s production using thesame personnel, equipment, and batch of bulk gas.

6.6 In the case of a medicinal gas produced by mixing two or more dif-ferent gases in a cylinder from the same manifold, at least one cylin-der from each manifold filling operation cycle should be tested for iden-tity, assay and if necessary water content of all of the component gasesand for identity of the balance gas in the mixture. When cylinders are


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filled individually, every cylinder should be tested for identity and assayof all of the component gases and at least one cylinder of each uninter-rupted filling cycle should be tested for identity of the balance gas in themixture.

6.7 When gases are mixed in-line before filling (e.g. nitrous oxide/oxygen mix-ture) continuous analysis of the mixture being filled is required.

6.8 When a cylinder is filled with more than one gas, the filling process mustensure that the gases are correctly mixed in every cylinder and are fullyhomogeneous.

6.9 Each filled cylinder should be tested for leaks using an appropriate method,prior to fitting the tamper evident seal. Where sampling and testing iscarried out the leak test should be completed after testing.

6.10 In the case of cryogenic gas filled into cryogenic home vessels for deliveryto users, each vessel should be tested for identity and assay.

6.11 Cryogenic vessels which are retained by customers and where themedicinal gas is refilled in place from dedicated mobile delivery tanksneed not be sampled after filling provided the filling company de-livers a certificate of analysis for a sample taken from the mobiledelivery tank. Cryogenic vessels retained by customers should be period-ically tested to confirm that the contents comply with Pharmacopoeialrequirements.

6.12 Retained samples are not required, unless otherwise specified.

7 Storage and Release

7.1 Filled cylinders should be held in quarantine until released by the qualifiedperson.

7.2 Gas cylinders should be stored under cover and not be subjected to extremesof temperature. Storage areas should be clean, dry, well ventilated and freeof combustible materials to ensure that cylinders remain clean up to thetime of use.

7.3 Storage arrangements should permit segregation of different gases and offull/empty cylinders and permit rotation of stock on a first in - first outbasis.

7.4 Gas cylinders should be protected from adverse weather conditions duringtransportation. Specific conditions for storage and transportation should beemployed for gas mixtures for which phase separation occurs on freezing.


Glossary

Definition of terms relating to manufacture of medicinal gases, which arenot given in the glossary of the current PIC/S Guide to GMP, but which areused in this Annex are given below.

Air separation plantAir separation plants take atmospheric air and through processes of purifi-cation, cleaning, compression, cooling, liquefaction and distillation sepa-rates the air into the gases oxygen, nitrogen and argon

AreaPart of premises that is specific to the manufacture of medicinal gases

Blowing downBlow the pressure down to atmospheric pressure

Bulk gasAny gas intended for medicinal use, which has completed all processing upto but not including final packaging

Compressed gasA gas which when packaged under pressure is entirely gaseous at –50◦C.(ISO 10286)

ContainerA container is a cryogenic vessel, a tank, a tanker, a cylinder, a cylinderbundle or any other package that is in direct contact with the medicinalgas

Cryogenic gasGas which liquefies at 1.013 bar at temperature below –150◦C

Cryogenic vesselA static or mobile thermally insulated container designed to contain lique-fied or cryogenic gases; the gas is removed in gaseous or liquid form

CylinderA transportable, pressure container with a water capacity not exceeding150 litres; in this document when using the word cylinder it includes cylin-der bundle (or cylinder pack) when appropriate

Cylinder bundleA set assembly of cylinders, which are fastened together in a frame andinterconnected by a manifold, transported and used as a unit

EvacuateTo remove the residual gas in a container by pulling a vacuum on it


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GasA substance or a mixture of substances that is completely gaseous at1013 bar (101,325 kPa) and +15◦C or has a vapour pressure exceeding3 bar (300 kPa) at +50◦C. (ISO 10286)

Hydrostatic pressure testTest performed for safety reasons as required by national or internationalguideline in order to make sure that cylinders or tanks can withhold highpressures

Liquefied gasA gas which when packaged under pressure, is partially liquid (gas over aliquid) at –50◦C

ManifoldEquipment or apparatus designed to enable one or more gas containers tobe emptied and filled at a time

Maximum theoretical residual impurityGaseous impurity coming from a possible retro-pollution and remainingafter the cylinders pre-treatment before filling. The calculation of the max-imum theoretical impurity is only relevant for compressed gases and sup-poses that these gases act as perfect gases

Medicinal gasAny gas or mixture of gases intended to be administered to patients fortherapeutic, diagnostic or prophylactic purposes using pharmacologicalaction and classified as a medicinal product

Minimum pressure retention valveValve equipped with a non-return system which maintains a definite pres-sure (about 3 to 5 bar over atmospheric pressure) in order to prevent con-tamination during use

Non-return valveValve which permits flow in one direction only

PurgeTo empty and clean a cylinder

� by blowing down and evacuatingor

� by blowing down, partial pressurisation with the gas in question andthen blowing down


TankStatic container for the storage of liquefied or cryogenic gas

TankerContainer fixed on a vehicle for the transport of liquefied or cryogenic gas

ValveDevice for opening and closing containers


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ANNEX 7 MANUFACTURE OF HERBAL MEDICINAL PRODUCTS

Principle

Because of their often complex and variable nature, and the number andsmall quantity of defined active ingredients, control of starting materials,storage and processing assume particular importance in the manufactureof herbal medicinal products.

Premises

Storage areas

1 Crude (i.e. unprocessed) plants should be stored in separate areas. Thestorage area should be well ventilated and be equipped in such a way asto give protection against the entry of insects or other animals, especiallyrodents. Effective measures should be taken to prevent the spread of anysuch animals and micro-organisms brought in with the crude plant and toprevent cross-contamination. Containers should be located in such a wayas to allow free air circulation.

2 Special attention should be paid to the cleanliness and good maintenanceof the storage areas particularly when dust is generated.

3 Storage of plants, extracts, tinctures and other preparations may requirespecial conditions of humidity, temperature or light protection; these con-ditions should be provided and monitored.

Production area

4 Specific provisions should be taken during sampling, weighing, mixing andprocessing operations of crude plants whenever dust is generated, to facili-tate cleaning and to avoid cross-contamination, as for example, dust extrac-tion, dedicated premises, etc.

Documentation

Specifications for starting materials

5 Apart from the data described in General Guide (Section II, Chapter 4,point 4.11), specifications for medicinal crude plants should include, as faras possible:


� the botanical name (with, if appropriate, the name of the originator ofthe classification, e.g. Linnaeus);

� the details of the source of the plant (country or region of origin, andwhere applicable, cultivation, time of harvesting, collection procedures,possible pesticides used, etc.);

� whether the whole plant or only a part is used;� when a dried plant is purchased, the drying system should be specified;� the description of the plant and its macro and microscopical examina-

tion;� the suitable identification tests including, where appropriate, identifica-

tion tests for known active ingredients, or markers. A reference authenticspecimen should be available for identification purposes;

� the assay, where appropriate, of constituents of known therapeutic activ-ity or of markers;

� the methods suitable to determine possible pesticide contamination andlimits accepted;

� the tests to determine fungal and/or microbial contamination, includingaflatoxins and pest-infestations, and limits accepted;

� the tests for toxic metals and for likely contaminants and adulterants;� the tests for foreign materials.

Any treatment used to reduce fungal/microbial contamination or otherinfestation should be documented. Specifications for such proceduresshould be available and should include details of process, tests andlimits for residues.

Processing instructions

6 The processing instructions should describe the different operations carriedout upon the crude plant such as drying, crushing and sifting, and includedrying time and temperatures, and methods used to control fragment orparticle size. It should also describe security sieving or other methods ofremoving foreign materials.

For the production of a vegetable drug preparation, instructions shouldinclude details of base or solvent, time and temperatures of extraction,details of any concentration stages and methods used (see also the note forguidance “Quality of herbal remedies”, Volume III of The rules governingmedicinal products in the European Union).

Sampling

7 Due to the fact that crude drugs are an aggregate of individual plants andcontain an element of heterogeneity, their sampling has to be carried out


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with special care by personnel with particular expertise. Each batch shouldbe identified by its own documentation.

Quality Control

8 Quality Control personnel should have particular expertise in herbalmedicinal products in order to be able to carry out identification testsand recognise adulteration, the presence of fungal growth, infestations,non-uniformity within a delivery of crude plants, etc.

9 The identity and quality of vegetable drug preparations and of finishedproduct should be tested as described in the note for guidance “Quality ofherbal remedies”.


ANNEX 8 SAMPLING OF STARTING ANDPACKAGING MATERIALS

Principle

Sampling is an important operation in which only a small fraction of a batchis taken. Valid conclusions on the whole cannot be based on tests whichhave been carried out on non-representative samples. Correct sampling isthus an essential part of a system of Quality Assurance.

Note: Sampling is dealt with in Chapter 6 of the Guide, items 6.11–6.14. This annex gives additional guidance on the sampling of starting andpackaging materials.

Personnel

1 Personnel who take samples should receive initial and on-going regulartraining in the disciplines relevant to correct sampling. This training shouldinclude:

� sampling plans;� written sampling procedures;� the techniques and equipment for sampling;� the risks of cross-contamination;� the precautions to be taken with regard to unstable and/or sterile sub-

stances;� the importance of considering the visual appearance of materials, con-

tainers and labels;� the importance of recording any unexpected or unusual circumstances.

Starting Materials

2 The identity of a complete batch of starting materials can normally only beensured if individual samples are taken from all the containers and an iden-tity test performed on each sample. It is permissible to sample only a pro-portion of the containers where a validated procedure has been establishedto ensure that no single container of starting material has been incorrectlylabelled.

3 This validation should take account of at least the following aspects:

� the nature and status of the manufacturer and of the supplier and theirunderstanding of the GMP requirements of the Pharmaceutical Industry;


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� the Quality Assurance system of the manufacturer of the startingmaterial;

� the manufacturing conditions under which the starting material isproduced and controlled;

� the nature of the starting material and the medicinal products in whichit will be used.

Under such a system, it is possible that a validated procedure exemptingidentity testing of each incoming container of starting material could beaccepted for:

� starting materials coming from a single product manufacturer or plant;� starting materials coming directly from a manufacturer or in the manu-

facturer’s sealed container where there is a history of reliability and regu-lar audits of the manufacturer’s Quality Assurance system are conductedby the purchaser (the manufacturer of the medicinal product) or by anofficially accredited body.

It is improbable that a procedure could be satisfactorily validated for:

� starting materials supplied by intermediaries such as brokers where thesource of manufacture is unknown or not audited;

� starting materials for use in parenteral products.

4 The quality of a batch of starting materials may be assessed by takingand testing a representative sample. The samples taken for identity test-ing could be used for this purpose. The number of samples taken for thepreparation of a representative sample should be determined statisticallyand specified in a sampling plan. The number of individual samples whichmay be blended to form a composite sample should also be defined, takinginto account the nature of the material, knowledge of the supplier and thehomogeneity of the composite sample.

Packaging Material

5 The sampling plan for packaging materials should take account of at leastthe following: the quantity received, the quality required, the nature of thematerial (e.g. primary packaging materials and/or printed packaging mater-ials), the production methods, and what is known of the Quality Assur-ance system of the packaging materials manufacturer based on audits. Thenumber of samples taken should be determined statistically and specifiedin a sampling plan.


ANNEX 9 MANUFACTURE OF LIQUIDS,CREAMS AND OINTMENTS

Principle

Liquids, creams and ointments may be particularly susceptible to microbialand other contamination during manufacture. Therefore special measuresmust be taken to prevent any contamination.


1 The use of closed systems for processing and transfer is recommended inorder to protect the product from contamination. Production areas wherethe products or open clean containers are exposed should normally beeffectively ventilated with filtered air.

2 Tanks, containers, pipework and pumps should be designed and installedso that they may be readily cleaned and if necessary sanitised. In particular,equipment design should include a minimum of dead-legs or sites whereresidues can accumulate and promote microbial proliferation.

3 The use of glass apparatus should be avoided wherever possible. Highquality stainless steel is often the material of choice for parts coming intocontact with product.

Production

4 The chemical and microbiological quality of water used in productionshould be specified and monitored. Care should be taken in the mainte-nance of water systems in order to avoid the risk of microbial proliferation.After any chemical sanitisation of the water systems, a validated flushingprocedure should be followed to ensure that the sanitising agent has beeneffectively removed.

5 The quality of materials received in bulk tankers should be checked beforethey are transferred to bulk storage tanks.

6 Care should be taken when transferring materials via pipelines to ensurethat they are delivered to their correct destination.

7 Materials likely to shed fibres or other contaminants, like cardboard orwooden pallets, should not enter the areas where products or clean con-tainers are exposed.


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8 Care should be taken to maintain the homogeneity of mixtures, suspen-sions, etc. during filling. Mixing and filling processes should be validated.Special care should be taken at the beginning of a filling process, afterstoppages and at the end of the process to ensure that homogeneity ismaintained.

9 When the finished product is not immediately packaged, the maximumperiod of storage and the storage conditions should be specified andadhered to.


ANNEX 10 MANUFACTURE OF PRESSURISED METERED DOSEAEROSOL PREPARATIONS FOR INHALATION

Principle

The manufacture of pressurised aerosol products for inhalation with meter-ing valves requires special consideration because of the particular nature ofthis form of product. It should be done under conditions which minimisemicrobial and particulate contamination. Assurance of the quality of thevalve components and, in the case of suspensions, of uniformity is also ofparticular importance.

General

1 There are presently two common manufacturing and filling methods asfollows:

(a) Two-shot system (pressure filling). The active ingredient is suspendedin a high boiling point propellant, the dose is put into the container, thevalve is crimped on and the lower boiling point propellant is injectedthrough the valve stem to make up the finished product. The suspensionof active ingredient in propellant is kept cool to reduce evaporation loss.

(b) One-shot process (cold filling). The active ingredient is suspended ina mixture of propellants and held either under high pressure or at alow temperature, or both. The suspension is then filled directly into thecontainer in one shot.


2 Manufacture and filling should be carried out as far as possible in a closedsystem.

3 Where products or clean components are exposed, the area should be fedwith filtered air, should comply with the requirements of at least a GradeD environment and should be entered through airlocks.

Production and Quality Control

4 Metering valves for aerosols are more complex pieces of engineeringthan most items used in pharmaceutical production. Their specifications,


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sampling and testing should recognise this. Auditing the Quality Assurancesystem of the valve manufacturer is of particular importance.

5 All fluids (e.g. liquid or gaseous propellants) should be filtered to removeparticles greater than 0.2 micron. An additional filtration where possibleimmediately before filling is desirable.

6 Containers and valves should be cleaned using a validated procedure appro-priate to the use of the product to ensure the absence of any contaminantssuch as fabrication aids (e.g. lubricants) or undue microbiological contam-inants. After cleaning, valves should be kept in clean, closed containersand precautions taken not to introduce contamination during subsequenthandling, e.g. taking samples. Containers should be fed to the filling linein a clean condition or cleaned on line immediately before filling.

7 Precautions should be taken to ensure uniformity of suspensions at thepoint of fill throughout the filling process.

8 When a two-shot filling process is used, it is necessary to ensure that bothshots are of the correct weight in order to achieve the correct composition.For this purpose, 100% weight checking at each stage is often desirable.

9 Controls after filling should ensure the absence of undue leakage. Anyleakage test should be performed in a way which avoids microbial con-tamination or residual moisture.


ANNEX 11 COMPUTERISED SYSTEMS

Principle

The introduction of computerised systems into systems of manufacturing,including storage, distribution and quality control does not alter the needto observe the relevant principles given elsewhere in the Guide. Wherea computerised system replaces a manual operation, there should be noresultant decrease in product quality or quality assurance. Considerationshould be given to the risk of losing aspects of the previous system whichcould result from reducing the involvement of operators.

Personnel

1 It is essential that there is the closest co-operation between key personneland those involved with computer systems. Persons in responsible posi-tions should have the appropriate training for the management and use ofsystems within their field of responsibility which utilises computers. Thisshould include ensuring that appropriate expertise is available and used toprovide advice on aspects of design, validation, installation and operationof computerised system.

Validation

2 The extent of validation necessary will depend on a number of factorsincluding the use to which the system is to be put, whether the validationis to be prospective or retrospective and whether or not novel elementsare incorporated. Validation should be considered as part of the completelife cycle of a computer system. This cycle includes the stages of planning,specification, programming, testing, commissioning, documentation, oper-ation, monitoring and modifying.

System

3 Attention should be paid to the siting of equipment in suitable conditionswhere extraneous factors cannot interfere with the system.

4 A written detailed description of the system should be produced (includingdiagrams as appropriate) and kept up to date. It should describe the prin-ciples, objectives, security measures and scope of the system and the main


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features of the way in which the computer is used and how it interacts withother systems and procedures.

5 The software is a critical component of a computerised system. The userof such software should take all reasonable steps to ensure that it has beenproduced in accordance with a system of Quality Assurance.

6 The system should include, where appropriate, built-in checks of the correctentry and processing of data.

7 Before a system using a computer is brought into use, it should be thor-oughly tested and confirmed as being capable of achieving the desiredresults. If a manual system is being replaced, the two should be run inparallel for a time, as a part of this testing and validation.

8 Data should only be entered or amended by persons authorised to do so.Suitable methods of deterring unauthorised entry of data include the use ofkeys, pass cards, personal codes and restricted access to computer termi-nals. There should be a defined procedure for the issue, cancellation, andalteration of authorisation to enter and amend data, including the changingof personal passwords. Consideration should be given to systems allowingfor recording of attempts to access by unauthorised persons.

9 When critical data are being entered manually (for example the weightand batch number of an ingredient during dispensing), there should be anadditional check on the accuracy of the record which is made. This checkmay be done by a second operator or by validated electronic means.

10 The system should record the identity of operators entering or confirm-ing critical data. Authority to amend entered data should be restricted tonominated persons. Any alteration to an entry of critical data should beauthorised and recorded with the reason for the change. Considerationshould be given to building into the system the creation of a completerecord of all entries and amendments (an “audit trail”).

11 Alterations to a system or to a computer program should only be madein accordance with a defined procedure which should include provisionfor validating, checking, approving and implementing the change. Such analteration should only be implemented with the agreement of the personresponsible for the part of the system concerned, and the alteration shouldbe recorded. Every significant modification should be validated.

12 For quality auditing purposes, it should be possible to obtain clear printedcopies of electronically stored data.

13 Data should be secured by physical or electronic means against wilful oraccidental damage, in accordance with item 4.9 of the Guide. Stored datashould be checked for accessibility, durability and accuracy. If changes


are proposed to the computer equipment or its programs, the above men-tioned checks should be performed at a frequency appropriate to the stor-age medium being used.

14 Data should be protected by backing-up at regular intervals. Back-up datashould be stored as long as necessary at a separate and secure location.

15 There should be available adequate alternative arrangements for systemswhich need to be operated in the event of a breakdown. The time required tobring the alternative arrangements into use should be related to the possibleurgency of the need to use them. For example, information required toeffect a recall must be available at short notice.

16 The procedures to be followed if the system fails or breaks down shouldbe defined and validated. Any failures and remedial action taken should berecorded.

17 A procedure should be established to record and analyse errors and toenable corrective action to be taken.

18 When outside agencies are used to provide a computer service, there shouldbe a formal agreement including a clear statement of the responsibilities ofthat outside agency (see Section II, Chapter 7).

19 When the release of batches for sale or supply is carried out using a com-puterised system, the system should allow for only a Qualified Person torelease the batches and it should clearly identify and record the personreleasing the batches.


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ANNEX 12 USE OF IONISING RADIATION IN THEMANUFACTURE OF MEDICINAL PRODUCTS

Note: The holder of, or applicant for, a marketing authorisation for aproduct which includes irradiation as part of its processing should alsorefer to the note produced by the Committee for Proprietary MedicinalProducts giving guidance on “Ionising radiation in the manufacture ofmedicinal products”.

Introduction

Ionising radiation may be used during the manufacturing process for vari-ous purposes including the reduction of bioburden and the sterilisation ofstarting materials, packaging components or products and the treatmentof blood products.

There are two types of irradiation process: Gamma Irradiation from aradioactive source and high-energy Electron Irradiation (Beta radiation)from an accelerator.

Gamma Irradiation: two different processing modes may be employed:

(i) Batch mode: the product is arranged at fixed locations around the radi-ation source and cannot be loaded or unloaded while the radiationsource is exposed.

(ii) Continuous mode: an automatic system conveys the products into theradiation cell, past the exposed radiation source along a defined pathand at an appropriate speed, and out of the cell.

Electron Irradiation: the product is conveyed past a continuous or pulsedbeam of high energy electrons (Beta radiation) which is scanned back andforth across the product pathway.

Responsibilities

1 Treatment by irradiation may be carried out by the pharmaceutical manu-facturer or by an operator of a radiation facility under contract (a “contractmanufacturer”), both of whom must hold an appropriate manufacturingauthorisation.

2 The pharmaceutical manufacturer bears responsibility for the quality ofthe product including the attainment of the objective of irradiation. Thecontract operator of the radiation facility bears responsibility for ensuringthat the dose of radiation required by the manufacturer is delivered to theirradiation container (i.e. the outermost container in which the productsare irradiated).


3 The required dose including justified limits will be stated in the marketingauthorisation for the product.

Dosimetry

4 Dosimetry is defined as the measurement of the absorbed dose by the use ofdosimeters. Both understanding and correct use of the technique is essentialfor the validation, commissioning and control of the process.

5 The calibration of each batch of routine dosimeters should be traceable to anational or international standard. The period of validity of the calibrationshould be stated, justified and adhered to.

6 The same instrument should normally be used to establish the calibra-tion curve of the routine dosimeters and to measure the change in theirabsorbance after irradiation. If a different instrument is used, the absoluteabsorbance of each instrument should be established.

7 Depending on the type of dosimeter used, due account should be takenof possible causes of inaccuracy including the change in moisture content,change in temperature, time elapsed between irradiation and measurement,and the dose rate.

8 The wavelength of the instrument used to measure the change inabsorbance of dosimeters and the instrument used to measure their thick-ness should be subject to regular checks of calibration at intervals estab-lished on the basis of stability, purpose and usage.

Validation of the Process

9 Validation is the action of proving that the process, i.e. the delivery of theintended absorbed dose to the product, will achieve the expected results.The requirements for validation are given more fully in the note for guid-ance on “the use of ionising radiation in the manufacture of medicinalproducts.”

10 Validation should include dose mapping to establish the distribution ofabsorbed dose within the irradiation container when packed with productin a defined configuration.

11 An irradiation process specification should include at least the following:

(a) details of the packaging of the product;(b) the loading pattern(s) of product within the irradiation container. Par-

ticular care needs to be taken, when a mixture of products is allowed inthe irradiation container, that there is no under-dosing of dense product


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or shadowing of other products by dense product. Each mixed productarrangement must be specified and validated;

(c) the loading pattern of irradiation containers around the source (batchmode) or the pathway through the cell (continuous mode);

(d) maximum and minimum limits of absorbed dose to the product (andassociated routine dosimetry);

(e) maximum and minimum limits of absorbed dose to the irradiationcontainer and associated routine dosimetry to monitor this absorbeddose;

(f) other process parameters, including dose rate, maximum time of expo-sure, number of exposures, etc.

When irradiation is supplied under contract at least parts (d) and (e) of theirradiation process specification should form part of that contract.

Commissioning of the Plant

General

12 Commissioning is the exercise of obtaining and documenting evidence thatthe irradiation plant will perform consistently within predetermined lim-its when operated according to the process specification. In the context ofthis annex, predetermined limits are the maximum and minimum dosesdesigned to be absorbed by the irradiation container. It must not be pos-sible for variations to occur in the operation of the plant which give adose to the container outside these limits without the knowledge of theoperator.

13 Commissioning should include the following elements:

(a) design;(b) dose mapping;(c) documentation;(d) requirement for re-commissioning.

Gamma irradiators

DESIGN

14 The absorbed dose received by a particular part of an irradiation containerat any specific point in the irradiator depends primarily on the followingfactors:

(a) the activity and geometry of the source;(b) the distance from source to container;(c) the duration of irradiation controlled by the timer setting or conveyor

speed;


(d) the composition and density of material, including other products,between the source and the particular part of the container.

15 The total absorbed dose will in addition depend on the path of containersthrough a continuous irradiator or the loading pattern in a batch irradiator,and on the number of exposure cycles.

16 For a continuous irradiator with a fixed path or a batch irradiator with afixed loading pattern, and with a given source strength and type of product,the key plant parameter controlled by the operator is conveyor speed ortimer setting.

DOSE MAPPING

17 For the dose mapping procedure, the irradiator should be filled with irradi-ation containers packed with dummy products or a representative productof uniform density. Dosimeters should be placed throughout a minimumof three loaded irradiation containers which are passed through the irradi-ator, surrounded by similar containers or dummy products. If the productis not uniformly packed, dosimeters should be placed in a larger numberof containers.

18 The positioning of dosimeters will depend on the size of the irradiation con-tainer. For example, for containers up to 1 × 1 × 0.5 m, a three-dimensional20 cm grid throughout the container including the outside surfaces mightbe suitable. If the expected positions of the minimum and maximum doseare known from a previous irradiator performance characterisation, somedosimeters could be removed from regions of average dose and replacedto form a 10 cm grid in the regions of extreme dose.

19 The results of this procedure will give minimum and maximum absorbeddoses in the product and on the container surface for a given set of plantparameters, product density and loading pattern.

20 Ideally, reference dosimeters should be used for the dose mapping exercisebecause of their greater precision. Routine dosimeters are permissible butit is advisable to place reference dosimeters beside them at the expectedpositions of minimum and maximum dose and at the routine monitoringposition in each of the replicate irradiation containers. The observed valuesof dose will have an associated random uncertainty which can be estimatedfrom the variations in replicate measurements.

21 The minimum observed dose, as measured by the routine dosimeters, neces-sary to ensure that all irradiation containers receive the minimum requireddose will be set in the knowledge of the random variability of the routinedosimeters used.


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22 Irradiator parameters should be kept constant, monitored and recordedduring dose mapping. The records, together with the dosimetry results andall other records generated, should be retained.

Electron beam irradiators

DESIGN

23 The absorbed dose received by a particular portion of an irradiated productdepends primarily on the following factors:

(a) the characteristics of the beam, which are: electron energy, averagebeam current, scan width and scan uniformity;

(b) the conveyor speed;(c) the product composition and density;(d) the composition, density and thickness of material between the output

window and the particular portion of product;(e) the output window to container distance.

24 Key parameters controlled by the operator are the characteristics of thebeam and the conveyor speed.

DOSE MAPPING

25 For the dose-mapping procedure, dosimeters should be placed betweenlayers of homogeneous absorber sheets making up a dummy product, orbetween layers of representative products of uniform density, such that atleast ten measurements can be made within the maximum range of theelectrons. Reference should also be made to sections 18–21.

26 Irradiator parameters should be kept constant, monitored and recordedduring dose mapping. The records, together with the dosimetry results andall other records generated, should be retained.

Re-commissioning

27 Commissioning should be repeated if there is a change to the process orthe irradiator which could affect the dose distribution to the irradiationcontainer (e.g. change of source pencils). The extent to re-commissioningdepends on the extent of the change in the irradiator or the load that hastaken place. If in doubt, re-commission.

Premises

28 Premises should be designed and operated to segregate irradiated from non-irradiated containers to avoid their cross-contamination. Where materialsare handled within closed irradiation containers, it may not be necessary


to segregate pharmaceutical from non-pharmaceutical materials, providedthere is no risk of the former being contaminated by the latter.

Any possibility of contamination of the products by radionuclide fromthe source must be excluded.

Processing

29 Irradiation containers should be packed in accordance with the specifiedloading pattern(s) established during validation.

30 During the process, the radiation dose to the irradiation containers shouldbe monitored using validated dosimetry procedures. The relationshipbetween this dose and the dose absorbed by the product inside thecontainer must have been established during process validation and plantcommissioning.

31 Radiation indicators should be used as an aid to differentiating irradiatedfrom non-irradiated containers. They should not be used as the sole meansof differentiation or as an indication of satisfactory processing.

32 Processing of mixed loads of containers within the irradiation cell shouldonly be done when it is known from commissioning trials or otherevidence that the radiation dose received by individual containers remainswithin the limits specified.

33 When the required radiation dose is by design given during more thanone exposure or passage through the plant, this should be with theagreement of the holder of the marketing authorisation and occur withina predetermined time period. Unplanned interruptions during irradiationshould be notified to the holder of the marketing authorisation if thisextends the irradiation process beyond a previously agreed period.

34 Non-irradiated products must be segregated from irradiated products atall times. Methods of doing this include the use of radiation indicators(item 31) and appropriate design of premises (item 28).

Gamma irradiators

35 For continuous processing modes, dosimeters should be placed so that atleast two are exposed in the irradiation at all times.

36 For batch modes, at least two dosimeters should be exposed in positionsrelated to the minimum dose position.

37 For continuous process modes, there should be a positive indication of thecorrect position of the source and an interlock between source position and


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conveyor movement. Conveyor speed should be monitored continuouslyand recorded.

38 For batch process modes source movement and exposure times for eachbatch should be monitored and recorded.

39 For a given desired dose, the timer setting or conveyor speed requires adjust-ment for source decay and source additions. The period of validity of thesetting or speed should be recorded and adhered to.

Electron beam irradiators

40 A dosimeter should be placed on every container.

41 There should be continuous recording of average beam current, electronenergy, scan-width and conveyor speed. These variables, other than con-veyor speed, need to be controlled within the defined limits establishedduring commissioning since they are liable to instantaneous change.

Documentation

42 The numbers of containers received, irradiated and dispatched should bereconciled with each other and with the associated documentation. Anydiscrepancy should be reported and resolved.

43 The irradiation plant operator should certify in writing the range of dosesreceived by each irradiated container within a batch or delivery.

44 Process and control records for each irradiation batch should be checkedand signed by a nominated responsible person and retained. The methodand place of retention should be agreed between the plant operator andthe holder of the marketing authorisation.

45 The documentation associated with the validation and commissioning ofthe plant should be retained for one year after the expiry date or at least fiveyears after the release of the last product processed by the plant, whicheveris the longer.

Microbiological Monitoring

46 Microbiological monitoring is the responsibility of the pharmaceuticalmanufacturer. It may include environmental monitoring where productis manufactured and pre-irradiation monitoring of the product as specifiedin the marketing authorisation.


ANNEX 13 MANUFACTURE OF INVESTIGATIONALMEDICINAL PRODUCTS

Principle

Investigational medicinal products should be produced in accordance withthe principles and the detailed guidelines of Good Manufacturing Prac-tice for Medicinal Products (The Rules Governing Medicinal Products inThe European Community, Volume IV). Other guidelines published by theEuropean Commission should be taken into account where relevant and asappropriate to the stage of development of the product. Procedures needto be flexible to provide for changes as knowledge of the process increases,and appropriate to the stage of development of the product.

In clinical trials there may be added risk to participating subjects com-pared to patients treated with marketed products. The application of GMPto the manufacture of investigational medicinal products is intended toensure that trial subjects are not placed at risk, and that the results ofclinical trials are unaffected by inadequate safety, quality or efficacy aris-ing from unsatisfactory manufacture. Equally, it is intended to ensure thatthere is consistency between batches of the same investigational medicinalproduct used in the same or different clinical trials, and that changes dur-ing the development of an investigational medicinal product are adequatelydocumented and justified.

The production of investigational medicinal products involves addedcomplexity in comparison to marketed products by virtue of the lackof fixed routines, variety of clinical trial designs, consequent packagingdesigns, the need, often, for randomisation and blinding and increased riskof product cross-contamination and mix up. Furthermore, there may beincomplete knowledge of the potency and toxicity of the product and alack of full process validation, or, marketed products may be used whichhave been re-packaged or modified in some way.

These challenges require personnel with a thorough understanding of,and training in, the application of GMP to investigational medicinal prod-ucts. Co-operation is required with trial sponsors who undertake the ulti-mate responsibility for all aspects of the clinical trial including the qualityof investigational medicinal products. The increased complexity in manu-facturing operations requires a highly effective quality system.

The annex also includes guidance on ordering, shipping, and returningclinical supplies, which are at the interface with, and complementary to,guidelines on Good Clinical Practice.

Note: Products other than the test product, placebo or comparator may besupplied to subjects participating in a trial. Such products may be used assupport or escape medication for preventative, diagnostic or therapeutic


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reasons and/or needed to ensure that adequate medical care is providedfor the subject. They may also be used in accordance with the protocolto induce a physiological response. These products do not fall within thedefinition of investigational medicinal products and may be supplied bythe sponsor, or the investigator. The sponsor should ensure that they are inaccordance with the notification/request for authorisation to conduct thetrial and that they are of appropriate quality for the purposes of the trialtaking into account the source of the materials, whether or not they are thesubject of a marketing authorisation and whether they have been repack-aged. The advice and involvement of a Qualified Person is recommendedin this task.

Glossary

BlindingA procedure in which one or more parties to the trial are kept unawareof the treatment assignment(s). Single-blinding usually refers to the sub-ject(s) being unaware, and double-blinding usually refers to the subject(s),investigator(s), monitor, and, in some cases, data analyst(s) being unawareof the treatment assignment(s). In relation to an investigational medicinalproduct, blinding shall mean the deliberate disguising of the identity ofthe product in accordance with the instructions of the sponsor. Unblindingshall mean the disclosure of the identity of blinded products.

Clinical trialAny investigation in human subjects intended to discover or verify the clin-ical, pharmacological and/or other pharmacodynamic effects of an inves-tigational product(s) and/or to identify any adverse reactions to an investi-gational product(s), and/or to study absorption, distribution, metabolism,and excretion of one or more investigational medicinal product(s) with theobject of ascertaining its/their safety and/or efficacy.

Comparator productAn investigational or marketed product (i.e. active control), or placebo,used as a reference in a clinical trial.

Investigational medicinal productA pharmaceutical form of an active substance or placebo being tested orused as a reference in a clinical trial, including a product with a marketingauthorisation when used or assembled (formulated or packaged) in a waydifferent from the authorised form, or when used for an unauthorisedindication, or when used to gain further information about the authorisedform.


Immediate packagingThe container or other form of packaging immediately in contact with themedicinal or investigational medicinal product.

InvestigatorA person responsible for the conduct of the clinical trial at a trial site. Ifa trial is conducted by a team of individuals at a trial site, the investigatoris the responsible leader of the team and may be called the principalinvestigator.

Manufacturer/importer of Investigational Medicinal ProductsAny holder of the authorisation to manufacture/import referred to in Arti-cle 13.1 of Directive 2001/20/EC.

OrderInstruction to process, package and/or ship a certain number of units ofinvestigational medicinal product(s).

Outer packagingThe packaging into which the immediate container is placed.

Product Specification FileA reference file containing, or referring to files containing, all the infor-mation necessary to draft the detailed written instructions on processing,packaging, quality control testing, batch release and shipping of an inves-tigational medicinal product.

RandomisationThe process of assigning trial subjects to treatment or control groups usingan element of chance to determine the assignments in order to reduce bias.

Randomisation CodeA listing in which the treatment assigned to each subject from the randomi-sation process is identified.

ShippingThe operation of packaging for shipment and sending of ordered medicinalproducts for clinical trials.

SponsorAn individual, company, institution or organisation which takes responsi-bility for the initiation, management and/or financing of a clinical trial.

Quality Management

1 The Quality System, designed, set up and verified by the manufactureror importer, should be described in written procedures available to thesponsor, taking into account the GMP principles and guidelines applicableto investigational medicinal products.


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2 The product specifications and manufacturing instructions may be changedduring development but full control and traceability of the changes shouldbe maintained.

Personnel

3 All personnel involved with investigational medicinal products should beappropriately trained in the requirements specific to these types of product.

4 The Qualified Person should in particular be responsible for ensuring thatthere are systems in place that meet the requirements of this Annex andshould therefore have a broad knowledge of pharmaceutical developmentand clinical trial processes. Guidance for the Qualified Person in connec-tion with the certification of investigational medicinal products is given inparagraphs 38 to 41.


5 The toxicity, potency and sensitising potential may not be fully under-stood for investigational medicinal products and this reinforces the needto minimise all risks of cross-contamination. The design of equipment andpremises, inspection/ test methods and acceptance limits to be used aftercleaning should reflect the nature of these risks. Consideration should begiven to campaign working where appropriate. Account should be takenof the solubility of the product in decisions about the choice of cleaningsolvent.

Documentation

Specifications and instructions

6 Specifications (for starting materials, primary packaging materials, inter-mediate, bulk products and finished products), manufacturing formulaeand processing and packaging instructions should be as comprehensiveas possible given the current state of knowledge. They should be periodi-cally re-assessed during development and updated as necessary. Each newversion should take into account the latest data, current technology used,regulatory and pharmacopoeial requirements, and should allow traceabil-ity to the previous document. Any changes should be carried out accordingto a written procedure, which should address any implications for productquality such as stability and bio-equivalence.


7 Rationales for changes should be recorded and the consequences of achange on product quality and on any on-going clinical trials should beinvestigated and documented.

Order

8 The order should request the processing and/or packaging of a certainnumber of units and/or their shipping and be given by or on behalf ofthe sponsor to the manufacturer. It should be in writing (though it may betransmitted by electronic means), and precise enough to avoid any ambigu-ity. It should be formally authorised and refer to the Product SpecificationFile and the relevant clinical trial protocol as appropriate.

Product Specification File

9 The Product Specification File (see glossary) should be continually updatedas development of the product proceeds, ensuring appropriate traceabil-ity to the previous versions. It should include, or refer to, the followingdocuments:

� Specifications and analytical methods for starting materials, packagingmaterials, intermediate, bulk and finished product;

� Manufacturing methods;� In-process testing and methods;� Approved label copy;� Relevant clinical trial protocols and randomisation codes, as appro-

priate;� Relevant technical agreements with contract givers, as appropriate;� Stability data;� Storage and shipment conditions.

The above listing is not intended to be exclusive or exhaustive. The con-tents will vary depending on the product and stage of development. Theinformation should form the basis for assessment of the suitability for cer-tification and release of a particular batch by the Qualified Person andshould therefore be accessible to him/her. Where different manufacturingsteps are carried out at different locations under the responsibility of dif-ferent Qualified Persons, it is acceptable to maintain separate files limitedto information of relevance to the activities at the respective locations.

Manufacturing Formulae and Processing Instructions

10 For every manufacturing operation or supply there should be clear andadequate written instructions and written records. Where an operationis not repetitive it may not be necessary to produce Master Formulae and


I II I

Processing Instructions. Records are particularly important for the prepara-tion of the final version of the documents to be used in routine manufactureonce the marketing authorisation is granted.

11 The information in the Product Specification File should be used to producethe detailed written instructions on processing, packaging, quality controltesting, storage conditions and shipping.

Packaging Instructions

12 Investigational medicinal products are normally packed in an individualway for each subject included in the clinical trial. The number of units to bepackaged should be specified prior to the start of the packaging operations,including units necessary for carrying out quality control and any retentionsamples to be kept. Sufficient reconciliations should take place to ensurethe correct quantity of each product required has been accounted for ateach stage of processing.

Processing, testing and packaging batch records

13 Batch records should be kept in sufficient detail for the sequence of opera-tions to be accurately determined. These records should contain anyrelevant remarks which justify the procedures used and any changesmade, enhance knowledge of the product and develop the manufacturingoperations.

14 Batch manufacturing records should be retained at least for the periodsspecified in Directive 91/356 as amended for investigational medicinalproducts.

Production

Packaging materials

15 Specifications and quality control checks should include measures to guardagainst unintentional unblinding due to changes in appearance betweendifferent batches of packaging materials.

Manufacturing operations

16 During development critical parameters should be identified and in-processcontrols primarily used to control the process. Provisional productionparameters and in-process controls may be deduced from prior expe-rience, including that gained from earlier development work. Carefulconsideration by key personnel is called for in order to formulate the nec-essary instructions and to adapt them continually to the experience gained


in production. Parameters identified and controlled should be justifiablebased on knowledge available at the time.

17 Production processes for investigational medicinal products are notexpected to be validated to the extent necessary for routine productionbut premises and equipment are expected to be validated. For sterile prod-ucts, the validation of sterilising processes should be of the same standardas for products authorised for marketing.

Likewise, when required, virus inactivation/removal and that of otherimpurities of biological origin should be demonstrated, to assure the safetyof biotechnologically derived products, by following the scientific princi-ples and techniques defined in the available guidance in this area.

18 Validation of aseptic processes presents special problems when the batchsize is small; in these cases the number of units filled may be the maximumnumber filled in production. If practicable, and otherwise consistent withsimulating the process, a larger number of units should be filled with mediato provide greater confidence in the results obtained. Filling and sealing isoften a manual or semi-automated operation presenting great challengesto sterility so enhanced attention should be given to operator training, andvalidating the aseptic technique of individual operators.

Principles applicable to comparator product

19 If a product is modified, data should be available (e.g. stability, compara-tive dissolution, bioavailability) to demonstrate that these changes do notsignificantly alter the original quality characteristics of the product.

20 The expiry date stated for the comparator product in its original packag-ing might not be applicable to the product where it has been repackagedin a different container that may not offer equivalent protection, or becompatible with the product. A suitable use by date, taking into accountthe nature of the product, the characteristics of the container and the stor-age conditions to which the article may be subjected, should be determinedby or on behalf of the sponsor. Such a date should be justified and mustnot be later than the expiry date of the original package. There should becompatibility of expiry dating and clinical trial duration.

Blinding operations

21 Where products are blinded, systems should be in place to ensure thatthe blind is achieved and maintained while allowing for identification of“blinded” products when necessary, including the batch numbers of theproducts before the blinding operation. Rapid identification of productshould also be possible in an emergency.


I II I

Randomisation code

22 Procedures should describe the generation, security, distribution, handlingand retention of any randomisation code used for packaging investiga-tional products, and code-break mechanisms. Appropriate records shouldbe maintained.

Packaging

23 During packaging of investigational medicinal products, it may be neces-sary to handle different products on the same packaging line at the sametime. The risk of product mix-up must be minimised by using appropriateprocedures and/or, specialised equipment as appropriate and relevant stafftraining.

24 Packaging and labelling of investigational medicinal products are likely tobe more complex and more liable to errors (which are also harder to detect)than for marketed products, particularly when “blinded” products withsimilar appearance are used. Precautions against mis-labelling such as labelreconciliation, line clearance, in-process control checks by appropriatelytrained staff should accordingly be intensified.

25 The packaging must ensure that the investigational medicinal productremains in good condition during transport and storage at intermediatedestinations. Any opening or tampering of the outer packaging duringtransport should be readily discernible.

Labelling

26 Table 1 summarises the contents of articles 26-30 that follow. Labellingshould comply with the requirements of Directive 91/356 as amended forInvestigational Medicinal Products. The following information should beincluded on labels, unless its absence can be justified, e.g. use of a centralisedelectronic randomisation system:

(a) name, address and telephone number of the sponsor, contract researchorganisation or investigator (the main contact for information on theproduct, clinical trial and emergency unblinding);

(b) pharmaceutical dosage form, route of administration, quantity ofdosage units, and in the case of open trials, the name/identifier andstrength/potency;

(c) the batch and/or code number to identify the contents and packagingoperation;

(d) a trial reference code allowing identification of the trial, site, investiga-tor and sponsor if not given elsewhere;


(e) the trial subject identification number/treatment number and whererelevant, the visit number;

(f) the name of the investigator (if not included in (a) or (d));(g) directions for use (reference may be made to a leaflet or other explana-

tory document intended for the trial subject or person administeringthe product);

(h) “For clinical trial use only” or similar wording;(i) the storage conditions;(j) period of use (use-by date, expiry date or re-test date as applicable), in

month/year format and in a manner that avoids any ambiguity;(k) “keep out of reach of children” except when the product is for use in

trials where the product is not taken home by subjects.

27 The address and telephone number of the main contact for informationon the product, clinical trial and for emergency unblinding need notappear on the label where the subject has been given a leaflet or cardwhich provides these details and has been instructed to keep this in theirpossession at all times.

28 Particulars should appear in the official language(s) of the country inwhich the investigational medicinal product is to be used. The particularslisted in Article 26 should appear on the immediate container and on theouter packaging (except for immediate containers in the cases described inArticles 29 and 30). The requirements with respect to the contents of thelabel on the immediate container and outer packaging are summarised inTable 1. Other languages may be included.

29 When the product is to be provided to the trial subject or the personadministering the medication within an immediate container togetherwith outer packaging that is intended to remain together, and the outerpackaging carries the particulars listed in paragraph 26, the followinginformation shall be included on the label of the immediate container (orany sealed dosing device that contains the immediate container):

(a) name of sponsor, contract research organisation or investigator;(b) pharmaceutical dosage form, route of administration (may be excluded

for oral solid dose forms), quantity of dosage units and in the case ofopen label trials, the name/identifier and strength/potency;

(c) batch and/or code number to identify the contents and packagingoperation;

(d) a trial reference code allowing identification of the trial, site,investigator and sponsor if not given elsewhere;

(e) the trial subject identification number/treatment number and whererelevant, the visit number.

30 If the immediate container takes the form of blister packs or small unitssuch as ampoules on which the particulars required in paragraph 26


I II I

cannot be displayed, outer packaging should be provided bearing a labelwith those particulars. The immediate container should neverthelesscontain the following:

(a) name of sponsor, contract research organisation or investigator;(b) route of administration (may be excluded for oral solid dose forms) and

in the case of open label trials, the name/identifier and strength/potency;(c) batch and/or code number to identify the contents and packaging

operation;(d) a trial reference code allowing identification of the trial, site,

investigator and sponsor if not given elsewhere;(e) the trial subject identification number/treatment number and where

relevant, the visit number.

31 Symbols or pictograms may be included to clarify certain informationmentioned above. Additional information, warnings and/or handlinginstructions may be displayed.

32 For clinical trials with the characteristics identified in Article 14 ofDirective 2001/20/EC, the following particulars should be added to theoriginal container but should not obscure the original labelling:

(i) name of sponsor, contract research organisation or investigator;(ii) trial reference code allowing identification of the trial site, investigator

and trial subject.

33 If it becomes necessary to change the use-by date, an additional labelshould be affixed to the investigational medicinal product. This additionallabel should state the new use-by date and repeat the batch number. It maybe superimposed on the old use-by date, but for quality control reasons,not on the original batch number. This operation should be performed atan appropriately authorised manufacturing site. However, when justified,it may be performed at the investigational site by or under the supervisionof the clinical trial site pharmacist, or other health care professional inaccordance with national regulations. Where this is not possible, it maybe performed by the clinical trial monitor(s) who should be appropriatelytrained. The operation should be performed in accordance with GMPprinciples, specific and standard operating procedures and under contract,if applicable, and should be checked by a second person. This additionallabelling should be properly documented in both the trial documentationand in the batch records.

Quality Control

34 As processes may not be standardised or fully validated, testing takes onmore importance in ensuring that each batch meets its specification.


35 Quality control should be performed in accordance with the Product Spec-ification File and in accordance with the information notified pursuant toArticle 9(2) of Directive 2001/20/EC. Verification of the effectiveness ofblinding should be performed and recorded.

36 Samples of each batch of investigational medicinal product, includingblinded product should be retained for the periods specified in Directive91/356 as amended for investigational medicinal products.

37 Consideration should be given to retaining samples from each packagingrun/trial period until the clinical report has been prepared to enable confir-mation of product identity in the event of, and as part of an investigationinto inconsistent trial results.

Release of Batches

38 Release of investigational medicinal products (see paragraph 43) should notoccur until after the Qualified Person has certified that the requirementsof Article 13.3 of Directive 2001/20/EC have been met (see paragraph39). The Qualified Person should take into account the elements listed inparagraph 40 as appropriate.

39 The duties of the Qualified Person in relation to investigational medicinalproducts are affected by the different circumstances that can arise andare referred to below. Table 2 summarises the elements that need to beconsidered for the most common circumstances:

(a)(i) Product manufactured within EU but not subject to an EU marketingauthorisation: the duties are laid down in Article 13.3(a) of Directive2001/20/EC.

(a) (ii) Product sourced from the open market within EU in accordancewith Article 80(b) of Directive 2001/83/EC and subject to an EUmarketing authorisation, regardless of manufacturing origin: theduties are as described above, however, the scope of certificationcan be limited to assuring that the products are in accordance withthe notification/request for authorisation to conduct the trial andany subsequent processing for the purpose of blinding, trial-specificpackaging and labelling. The Product Specification File will be sim-ilarly restricted in scope (see paragraph 9).

(b) Product imported directly from a third country: the duties are laiddown in Article 13.3(b) of Directive 2001/20/EC. Where investiga-tional medicinal products are imported from a third country andthey are subject to arrangements concluded between the Commu-nity and that country, such as a Mutual Recognition Agreement(MRA), equivalent standards of Good Manufacturing Practice apply


I II I

provided any such agreement is relevant to the product in question.In the absence of an MRA, the Qualified Person should determinethat equivalent standards of Good Manufacturing Practice applythrough knowledge of the quality system employed at the manufac-turer. This knowledge is normally acquired through participation inaudit of the manufacturer’s quality systems. In either case, the Qual-ified Person may then certify on the basis of documentation suppliedby the third country manufacturer (see paragraph 40).

(c) For imported comparator products where adequate assurance can-not be obtained in order to certify that each batch has been manufac-tured to equivalent standards of Good Manufacturing Practice, theduty of the Qualified Person is defined in Article 13.3(c) of Directive2001/20/EC.

40 Assessment of each batch for certification prior to release may include asappropriate:

� batch records, including control reports, in-process test reports andrelease reports demonstrating compliance with the product specificationfile, the order, protocol and randomisation code. These records shouldinclude all deviations or planned changes, and any consequent addi-tional checks or tests, and should be completed and endorsed by thestaff authorised to do so according to the quality system;

� production conditions;� the validation status of facilities, processes and methods; examination

of finished packs; where relevant, the results of any analyses or testsperformed after importation;

� stability reports;� the source and verification of conditions of storage and shipment;� audit reports concerning the quality system of the manufacturer;� documents certifying that the manufacturer is authorised to manufacture

investigational medicinal products or comparators for export by theappropriate authorities in the country of export;

� where relevant, regulatory requirements for marketing authorisation,GMP standards applicable and any official verification of GMP com-pliance;

� all other factors of which the QP is aware that are relevant to the qualityof the batch.

The relevance of the above elements is affected by the country of originof the product, the manufacturer, and the marketed status of the product(with or without a marketing authorisation, in the EU or in a third country)and its phase of development.

The sponsor should ensure that the elements taken into account bythe qualified person when certifying the batch are consistent with the


information notified pursuant to Article 9(2) of Directive 2001/20/EC (seealso paragraph 44).

41 Where investigational medicinal products are manufactured and packagedat different sites under the supervision of different Qualified Persons, therecommendations listed in Annex 16 to the GMP Guide should be followedas applicable.

42 Where, permitted in accordance with local regulations, packaging orlabelling is carried out at the investigator site by, or under the supervision ofa clinical trials pharmacist, or other health care professional as allowed inthose regulations, the Qualified Person is not required to certify the activityin question. The sponsor is nevertheless responsible for ensuring that theactivity is adequately documented and carried out in accordance with theprinciples of GMP and should seek the advice of the Qualified Person inthis regard.

Shipping

43 Shipping of investigational products should be conducted according toinstructions given by or on behalf of the sponsor in the shipping order.

44 Investigational medicinal products should remain under the control ofthe sponsor until after completion of a two-step release procedure: cer-tification by the Qualified Person; and release following fulfilment of therequirements of Article 9 (Commencement of a clinical trial) of Directive2001/20/EC. The sponsor should ensure that these are consistent with thedetails actually considered by the Qualified Person. Both releases shouldbe recorded and retained in the relevant trial files held by or on behalf ofthe sponsor.

45 De-coding arrangements should be available to the appropriate responsi-ble personnel before investigational medicinal products are shipped to theinvestigator site.

46 A detailed inventory of the shipments made by the manufacturer orimporter should be maintained. It should particularly mention theaddressees’ identification.

47 Transfers of investigational medicinal products from one trial site toanother should remain the exception. Such transfers should be coveredby standard operating procedures. The product history while outside ofthe control of the manufacturer, through for example, trial monitoringreports and records of storage conditions at the original trial site shouldbe reviewed as part of the assessment of the product’s suitability fortransfer and the advice of the Qualified person should be sought. Theproduct should be returned to the manufacturer, or another authorised


I II I

manufacturer for re-labelling, if necessary, and certification by a QualifiedPerson. Records should be retained and full traceability ensured.

Complaints

48 The conclusions of any investigation carried out in relation to a complaintwhich could arise from the quality of the product should be discussedbetween the manufacturer or importer and the sponsor (if different). Thisshould involve the Qualified Person and those responsible for the relevantclinical trial in order to assess any potential impact on the trial, productdevelopment and on subjects.

Recalls and Returns

Recalls

49 Procedures for retrieving investigational medicinal products and docu-menting this retrieval should be agreed by the sponsor, in collaborationwith the manufacturer or importer where different. The investigator andmonitor need to understand their obligations under the retrieval procedure.

50 The Sponsor should ensure that the supplier of any comparator or othermedication to be used in a clinical trial has a system for communicating tothe Sponsor the need to recall any product supplied.

Returns

51 Investigational medicinal products should be returned on agreed conditionsdefined by the sponsor, specified in approved written procedures.

52 Returned investigational medicinal products should be clearly identi-fied and stored in an appropriately controlled, dedicated area. Inventoryrecords of the returned medicinal products should be kept.

Destruction

53 The Sponsor is responsible for the destruction of unused and/or returnedinvestigational medicinal products. Investigational medicinal productsshould therefore not be destroyed without prior written authorisation bythe Sponsor.

54 The delivered, used and recovered quantities of product should be recorded,reconciled and verified by or on behalf of the Sponsor for each trial site andeach trial period. Destruction of unused investigational medicinal productsshould be carried out for a given trial site or a given trial period only after


any discrepancies have been investigated and satisfactorily explained andthe reconciliation has been accepted. Recording of destruction operationsshould be carried out in such a manner that all operations may be accountedfor. The records should be kept by the Sponsor.

55 When destruction of investigational medicinal products takes place a datedcertificate of, or receipt for destruction, should be provided to the Spon-sor. These documents should clearly identify, or allow traceability to,the batches and/or patient numbers involved and the actual quantitiesdestroyed.

SummaryTable 1 of labelling details (§26 to 30)

(a) name, address and telephone number of thesponsor, contract research organisation orinvestigator (the main contact for information on theproduct, clinical trial and emergency unblinding)

GENERALCASEFor both the outer packagingand immediate container (§26)

(b) pharmaceutical dosage form, route ofadministration, quantity of dosage units, and in thecase of open trials, the name/identifier andstrength/potency;(c) the batch and/or code number to identify thecontents and packaging operation;

Particularsa1 to k

(d) a trial reference code allowing identification ofthe trial, site, investigator and sponsor if not givenelsewhere;(e) the trial subject identification number/treatmentnumber and where relevant, the visit number;(f) the name of the investigator (if not included in (a)or (d));

IMMEDIATE CONTAINERWhere immediate container andouter packaging remain together

(§29)5

(g) directions for use (reference may be made to aleaflet or other explanatory document intended forthe trial subject or person administering the product); a2 b3 c d e(h) “for clinical trial use only” or similar wording;(i) the storage conditions;

(j) period of use (use-by date, expiry date or re-testdate as applicable), in month/year format and in amanner that avoids any ambiguity;

IMMEDIATE CONTAINERBlisters or small packaging units (§30)5

(k) “keep out of reach of children” except when theproduct is for use in trials where the product is nottaken home by subjects.

a2 b3,4 c d e

1 The address and telephone number of the main contact for information on the product, clinical trialand for emergency unblinding need not appear on the label where the subject has been given a leafletor card which provides these details and has been instructed to keep this in their possession at alltimes (§27).2 The address and telephone number of the main contact for information on the product, clinical trialand for emergency unblinding need not be included.3 Route of administration may be excluded for oral solid dose forms.4 The pharmaceutical dosage form and quantity of dosage units may be omitted.5 When the outer packaging carries the particulars listed in Article 26.

throughout

Table 2 Batch release of products

ELE

ME

NTS

TO B

E TA

KE

N IN

TO A

CC

OU

NT

(3)P

RO

DU

CT AVA

ILAB

LE IN

THE

EU

PR

OD

UC

T IMP

OR

TED

FRO

M TH

IRD

CO

UN

TRIE

S

Product

manufactured

inE

Uw

ithoutM

A

Productw

ithM

Aand

availableon

EU

market

Product

withoutany

EU

MA

Product

with

aE

UM

A

Com

paratorw

heredocum

entationcertifying

thateach

batchhas

beenm

anufacturedin

conditionsat

leastequivalenttothose

laiddow

nin

Directive

91/356/EE

Ccannotbe

obtainedB

EFO

RE

CLIN

ICA

L TRIA

L PR

OC

ES

SIN

G

a)Shipping

andstorage

conditionsYes

b)Allrelevant factors

(1)showing

thateachbatch

hasbeen

manufactured

andreleased

inaccordance

with:

Yes(2)

Directive

91/356/E

EC

,or–

Yes

GM

Pstandards

atleastequivalenttothose

laiddow

nin

Directive

91/356/E

EC

.

c)Docum

entationshow

ingthateach

batchhas

beenreleased

within

theE

Uaccording

toE

UG

MP

requirements

(seeD

irective2001/83/E

C,article

51),ordocumentation

showing

thattheproductis

availableon

theE

Um

arketandhas

beenprocured

inaccordance

with

article8

0(b)ofDirective

2001/83/EC

.

Yes

d)Docum

entationshow

ingthatthe

productisavailable

onthe

localmarketand

documentation

toestablish

confidencein

thelocalregulatory

requirements

formarketing

authorisationand

release for local use.

Yes

e)Results

ofallanalysis,testsand

checksperform

edto

assessthe

qualityofthe

imported

batchaccording

to:

therequirem

entsofthe

MA

(seeD

irective2001/83/E

C,article

51b),or–

Yes–

theP

roductSpecification

File,theO

rder,article9.2

submission

tothe

regulatoryauthorities.

Yes–

Yes

Where

theseanalyses

andtests

arenotperform

edin

theE

U,this

shouldbe

justifiedand

theQ

Pm

ustcertifythatthey

havebeen

carriedoutin

accordancew

ithG

MP

standardsatleastequivalent

tothose

laiddow

nin

Directive

91/356/E

EC

.

YesYes

Yes

AFTE

R C

LINIC

AL TR

IAL P

RO

CE

SS

ING

f)Inaddition

tothe

assessmentbefore

clinicaltrialprocessing,allfurtherrelevantfactors(1)

showing

thateachbatch

hasbeen

processedforthe

purposesofblinding,trial-specific

packaging,labelling

andtesting

inaccordance

with:

Directive

91/356/E

EC

, orYes

(2)

GM

Pstandards

atleastequivalenttothose

laiddow

nin

Directive

91/356/E

EC

.–

Yes(1)These

factorsare

summ

arisedin

paragraph4

0.(2)W

herean

MR

Aorsim

ilararrangements

arein

placecovering

theproducts

inquestion,equivalentstandards

ofGM

Papply.

(3)Inallcases

theinform

ationnotified

pursuanttoA

rticle9(2)ofD

irective2001/20/E

Cshould

beconsistentw

iththe

elements

actuallytaken

intoaccountby

theQ

Pw

hocertifies

thebatch

priortorelease.


ANNEX 14 MANUFACTURE OF MEDICINAL1 PRODUCTSDERIVED FROM HUMAN BLOOD OR PLASMA

Principle

In accordance with Directive 75/318/EEC2, for biological medicinal prod-ucts derived from human blood or plasma, starting materials include thesource materials such as cells or fluids including blood or plasma. Medic-inal products derived from human blood or plasma have certain specialfeatures arising from the biological nature of the source material. Forexample, disease-transmitting agents, especially viruses, may contaminatethe source material. The safety of these products relies therefore on thecontrol of source materials and their origin as well as on the subsequentmanufacturing procedures, including virus removal and inactivation.

The general chapters of the guide to GMP apply to medicinal productsderived from human blood or plasma, unless otherwise stated. Some ofthe Annexes may also apply, e.g. manufacture of sterile medicinal prod-ucts, use of ionising radiation in the manufacture of medicinal products,manufacture of biological medicinal products and computerised systems.Since the quality of the final products is affected by all the steps in theirmanufacture, including the collection of blood or plasma, all operationsshould, therefore, be done in accordance with an appropriate system ofQuality Assurance and current Good Manufacturing Practice.

By virtue of Directive 89/381/EEC, the necessary measures shall be takento prevent the transmission of infectious diseases and the requirements andstandards of the European Pharmacopoeia monographs regarding plasmafor fractionation and medicinal products derived from human blood orplasma shall be applicable. These measures shall also comprise the Coun-cil Recommendation of 29 June 1998 “On the suitability of blood andplasma donors and the screening of donated blood in the European Com-munity3 (98/463/EC), the recommendations of the Council of Europe (see

1 Council Directive 89/381/EEC of 14 June 1989 extending the scope of Directives65/65/EEC and 75/319/EEC on the approximation of provisions laid down bylaw, regulation or administrative action relating to proprietary medicinal prod-ucts and laying down special provisions for medicinal products derived fromhuman blood or human plasma (OJ No L 181 of 28.6.1989).

2 Council Directive 75/318/EEC, of 20 May 1975, on the approximation of thelaws of Member States relating to analytical, pharmacotoxicological and clinicalstandards and protocols in respect of the testing of medicinal products (OJ NoL 147 of 9.6.1975, p. 1) as last amended by Council Directive 93/39/EEC (OJNo L 214 of 24.8.1993, p. 22).

3 O.J. L 20321.7.1998 p. 14.


I II I

“Guide to the Preparation, Use and Quality Assurance of Blood Com-ponents”, Council of Europe Press) and the World Health Organization(see report by the WHO Expert Committee on Biological Standardisation,WHO Technical Report Series 840, 1994).

This annex should also be read in conjunction with the guidelinesadopted by the CPMP, in particular “Note for guidance on plasma-derivedmedicinal products (CPMP/BWP/269/95 rev.2)”, “Virus validation studies:the design, contribution and interpretation of studies validating the inacti-vation and removal of viruses” published in Volume 3A of the series “TheRules Governing Medicinal Products in the European Community”) and“Contribution to part II of the structure of the dossier for applications formarketing authorisation-control of starting materials for the productionof blood derivatives”(III/5272/94).

These documents are regularly revised and reference should be made tothe latest revisions for current guidance.

The provisions of this annex apply to medicinal products derived fromhuman blood and plasma. They do not cover blood components used intransfusion medicine, since these are presently not covered by EC directives.However many of these provisions may be applicable to such componentsand competent authorities may require compliance with them.

Glossary

BloodWhole blood collected from a single donor and processed either for trans-fusion or further manufacturing

Blood componentsTherapeutic components of blood (red cells, white cells, plasma, platelets),that can be prepared by centrifugation, filtration and freezing using con-ventional blood bank methodology

Medicinal product derived from blood or plasmaSame meaning as that given in Directive 89/381/EEC

Quality Management

1 Quality Assurance should cover all stages leading to the finished product,from collection (including donor selection, blood bags, anticoagulant solu-tions and test kits) to storage, transport, processing, quality control anddelivery of the finished product, all in accordance with the texts referredto under Principle at the beginning of this Annex.


2 Blood or plasma used as a source material for the manufacture of medicinalproducts should be collected by establishments and be tested in laboratorieswhich are subject to inspection and approved by a competent authority.

3 Procedures to determine the suitability of individuals to donate blood andplasma, used as a source material for the manufacture of medicinal prod-ucts, and the results of the testing of their donations should be documentedby the collection establishment and should be available to the manufacturerof the medicinal product.

4 Monitoring of the quality of medicinal products derived from human bloodor plasma should be carried out in such a way that any deviations fromthe quality specifications can be detected.

5 Medicinal products derived from human blood or plasma which have beenreturned unused should normally not be re-issued; (see also point 5.65 ofthe main GMP Guide).


6 The premises used for the collection of blood or plasma should be of suit-able size, construction and location to facilitate their proper operation,cleaning and maintenance. Collection, processing and testing of blood andplasma should not be performed in the same area. There should be suitabledonor interview facilities so that these interviews are carried out in private.

7 Manufacturing, collection and testing equipment should be designed, qual-ified and maintained to suit its intended purpose and should not presentany hazard. Regular maintenance and calibration should be carried outand documented according to established procedures.

8 In the preparation of plasma-derived medicinal products, viral inactivationor removal procedures are used and steps should be taken to prevent cross-contamination of treated with untreated products; dedicated and distinctpremises and equipment should be used for treated products.

Blood and Plasma Collection

9 A standard contract is required between the manufacturer of the medici-nal product derived from human blood or plasma and the blood/plasmacollection establishment or organisation responsible for collection. Guid-ance on the content of the standard contract is provided in “Contributionto part II of the structure of the dossier for applications for marketing


I II I

authorisation control of starting materials for the production of bloodderivatives” (III/5272/94).

10 Each donor must be positively identified at reception and again beforevenepuncture; see also Council Recommendation of 29 June 1998 on thesuitability of blood and plasma donors and the screening of donated bloodin the European Community4 (98/463/EC).

11 The method used to disinfect the skin of the donor should be clearly definedand shown to be effective. Adherence to that method should then be main-tained.

12 Donation number labels must be re-checked independently to ensure thatthose on blood packs, sample tubes and donation records are identical.

13 Blood bag and apheresis systems should be inspected for damage or con-tamination before being used to collect blood or plasma. In order to ensuretraceability, the batch number of blood bags and apheresis systems shouldbe recorded.

Traceability and Post Collection Measures

14 While fully respecting confidentiality, there must be a system in place whichenables the path taken by each donation to be traced, both forward fromthe donor and back from the finished medicinal product, including the cus-tomer (hospital or healthcare professional). It is normally the responsibilityof this customer to identify the recipient.

15 Post-collection measures: A standard operating procedure describing themutual information system between the blood/plasma collection establish-ment and the manufacturing/fractionation facility should be set up so thatthey can inform each other if, following donation:

� it is found that the donor did not meet the relevant donor health criteria;� a subsequent donation from a donor previously found negative for viral

markers is found positive for any of the viral markers;� it is discovered that testing for viral markers has not been carried out

according to agreed procedures;� the donor has developed an infectious disease caused by an agent poten-

tially transmissible by plasma-derived products (HBV, HCV, HAV andother non-A, non-B, non-C hepatitis viruses, HIV 1 and 2 and otheragents in the light of current knowledge);

� the donor develops Creutzfeldt-Jakob disease (CJD or vCJD);

4 O.J. L 20321.7.1998 p. 14.


� the recipient of blood or a blood component develops post-transfusion/infusion infection which implicates or can be traced backto the donor.

The procedures to be followed in the event of any of the above shouldbe documented in the standard operating procedure. Look-back shouldconsist of tracing back of previous donations for at least six months prior tothe last negative donation. In the event of any of the above, a re-assessmentof the batch documentation should always be carried out.

The need for withdrawal of the given batch should be carefully consid-ered, taking into account criteria such as the transmissible agent involved,the size of the pool, the time period between donation and seroconver-sion, the nature of the product and its manufacturing method. Wherethere are indications that a donation contributing to a plasma pool wasinfected with HIV or hepatitis A, B or C, the case should be referred tothe relevant competent authority(ies) responsible for the authorisation ofthe medicinal product and the company’s view regarding continued man-ufacture from the implicated pool or of the possibility of withdrawal ofthe product(s) should be given. More specific guidance is given in the cur-rent version of the CPMP Note for Guidance on Plasma-derived MedicinalProducts.

Production and Quality Control

16 Before any blood and plasma donations, or any product derived therefrom,are released for issue and/or fractionation, they should be tested, using avalidated test method of suitable sensitivity and specificity, for the followingmarkers of specific disease-transmitting agents:

� HBsAg;� antibodies to HIV 1 and HIV 2;� antibodies to HCV.

If a repeat-reactive result is found in any of these tests, the donation is notacceptable. (Additional tests may form part of national requirements)

17 The specified storage temperatures of blood, plasma and intermediate prod-ucts when stored and during transportation from collection establishmentsto manufacturers, or between different manufacturing sites, should bechecked and validated. The same applies to delivery of these products.

18 The first homogeneous plasma pool (e.g. after separation of the cryoprecip-itate) should be tested using a validated test method, of suitable sensitivityand specificity, and found non-reactive for the following markers of specificdisease-transmitting agents:


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� HBsAg;� antibodies to HIV 1 and HIV 2;� antibodies to HCV.

Confirmed positive pools must be rejected.

19 Only batches derived from plasma pools tested and found non-reactive forHCV RNA by nucleic acid amplification technology (NAT), using a vali-dated test method of suitable sensitivity and specificity, should be released.

20 Testing requirements for viruses, or other infectious agents, should be con-sidered in the light of knowledge emerging as to infectious agents and theavailability of appropriate test methods.

21 The labels on single units of plasma stored for pooling and fractionationmust comply with the provisions of the European Pharmacopoeia mono-graph “Human Plasma for Fractionation” and bear at least the identi-fication number of the donation, the name and address of the collectionestablishment or the references of the blood transfusion service responsiblefor preparation, the batch number of the container, the storage tempera-ture, the total volume or weight of plasma, the type of anticoagulant usedand the date of collection and/or separation.

22 In order to minimise the microbiological contamination of plasma for frac-tionation or the introduction of foreign material, the thawing and poolingshould be performed at least in a grade D clean area, wearing the appro-priate clothing and in addition face masks and gloves should be worn.Methods used for opening bags, pooling and thawing should be regularlymonitored, e.g. by testing for bioburden. The cleanroom requirements forall other open manipulations should conform to the requirements of Annex1 of the EU Guide to GMP.

23 Methods for clearly distinguishing between products or intermediateswhich have undergone a process of virus removal or inactivation, fromthose which have not, should be in place.

24 Validation of methods used for virus removal or virus inactivation shouldnot be conducted in the production facilities in order not to put the rou-tine manufacture at any risk of contamination with the viruses used forvalidation.

Retention of Samples

25 Where possible, samples of individual donations should be stored to facil-itate any necessary look-back procedure. This would normally be theresponsibility of the collection establishment. Samples of each pool of


plasma should be stored under suitable conditions for at least one yearafter the expiry date of the finished product with the longest shelf-life.

Disposal of Rejected Blood, Plasma or Intermediates

26 There should be a standard operating procedure for the safe and effectivedisposal of blood, plasma or intermediates.


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ANNEX 15 QUALIFICATION AND VALIDATION

Principle

1 This Annex describes the principles of qualification and validation whichare applicable to the manufacture of medicinal products. It is a require-ment of GMP that manufacturers identify what validation work is neededto prove control of the critical aspects of their particular operations. Sig-nificant changes to the facilities, the equipment and the processes, whichmay affect the quality of the product, should be validated. A risk assess-ment approach should be used to determine the scope and extent ofvalidation.

Planning for Validation

2 All validation activities should be planned. The key elements of a valida-tion programme should be clearly defined and documented in a validationmaster plan (VMP) or equivalent documents.

3 The VMP should be a summary document which is brief, concise and clear.

4 The VMP should contain data on at least the following:

(a) validation policy;(b) organisational structure of validation activities;(c) summary of facilities, systems, equipment and processes to be validated;(d) documentation format: the format to be used for protocols and reports;(e) planning and scheduling;(f) change control;(g) reference to existing documents.

5 In case of large projects, it may be necessary to create separate validationmaster plans.

Documentation

6 A written protocol should be established that specifies how qualificationand validation will be conducted. The protocol should be reviewed andapproved. The protocol should specify critical steps and acceptance criteria.

7 A report that cross-references the qualification and/or validation protocolshould be prepared, summarising the results obtained, commenting on anydeviations observed, and drawing the necessary conclusions, including rec-ommending changes necessary to correct deficiencies. Any changes to the


plan as defined in the protocol should be documented with appropriatejustification.

8 After completion of a satisfactory qualification, a formal release for thenext step in qualification and validation should be made as a writtenauthorisation.

Qualification

Design qualification

9 The first element of the validation of new facilities, systems or equipmentcould be design qualification (DQ).

10 The compliance of the design with GMP should be demonstrated and doc-umented.

Installation qualification

11 Installation qualification (IQ) should be performed on new or modifiedfacilities, systems and equipment.

12 IQ should include, but not be limited to the following:

(a) installation of equipment, piping, services and instrumentation checkedto current engineering drawings and specifications;

(b) collection and collation of supplier operating and working instructionsand maintenance requirements;

(c) calibration requirements;(d) verification of materials of construction.

Operational qualification

13 Operational qualification (OQ) should follow Installation qualification.

14 OQ should include, but not be limited to the following:

(a) tests that have been developed from knowledge of processes, systemsand equipment;

(b) tests to include a condition or a set of conditions encompassing upperand lower operating limits, sometimes referred to as “worst case” con-ditions.

15 The completion of a successful Operational qualification should allow thefinalisation of calibration, operating and cleaning procedures, operatortraining and preventative maintenance requirements. It should permit aformal “release” of the facilities, systems and equipment.


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Performance qualification

16 Performance qualification (PQ) should follow successful completion ofInstallation qualification and Operational qualification.

17 PQ should include, but not be limited to the following:

(a) tests, using production materials, qualified substitutes or simulatedproduct, that have been developed from knowledge of the process andthe facilities, systems or equipment;

(b) tests to include a condition or set of conditions encompassing upperand lower operating limits.

18 Although PQ is described as a separate activity, it may in some cases beappropriate to perform it in conjunction with OQ.

Qualification of established (in-use) facilities, systems and equipment

19 Evidence should be available to support and verify the operating param-eters and limits for the critical variables of the operating equipment.Additionally, the calibration, cleaning, preventative maintenance, operat-ing procedures and operator training procedures and records should bedocumented.

Process Validation

General

20 The requirements and principles outlined in this chapter are applicable tothe manufacture of pharmaceutical dosage forms. They cover the initialvalidation of new processes, subsequent validation of modified processesand re-validation.

21 Process validation should normally be completed prior to the distributionand sale of the medicinal product (prospective validation). In exceptionalcircumstances, where this is not possible, it may be necessary to validateprocesses during routine production (concurrent validation). Processes inuse for some time should also be validated (retrospective validation).

22 Facilities, systems and equipment to be used should have been qualifiedand analytical testing methods should be validated. Staff taking part in thevalidation work should have been appropriately trained.

23 Facilities, systems, equipment and processes should be periodically evalu-ated to verify that they are still operating in a valid manner.


Prospective validation

24 Prospective validation should include, but not be limited to the following:

(a) short description of the process;(b) summary of the critical processing steps to be investigated;(c) list of the equipment/facilities to be used (including measuring/

monitoring/recording equipment) together with its calibration status;(d) finished product specifications for release;(e) list of analytical methods, as appropriate;(f) proposed in-process controls with acceptance criteria;(g) additional testing to be carried out, with acceptance criteria and ana-

lytical validation, as appropriate;(h) sampling plan;(i) methods for recording and evaluating results;(j) functions and responsibilities;(k) proposed timetable.

25 Using this defined process (including specified components) a series ofbatches of the final product may be produced under routine conditions.In theory the number of process runs carried out and observations madeshould be sufficient to allow the normal extent of variation and trends tobe established and to provide sufficient data for evaluation. It is generallyconsidered acceptable that three consecutive batches/runs within the finallyagreed parameters, would constitute a validation of the process.

26 Batches made for process validation should be the same size as the intendedindustrial scale batches.

27 If it is intended that validation batches be sold or supplied, the conditionsunder which they are produced should comply fully with the requirementsof Good Manufacturing Practice, including the satisfactory outcome of thevalidation exercise, and with the marketing authorisation.

Concurrent validation

28 In exceptional circumstances it may be acceptable not to complete a vali-dation programme before routine production starts.

29 The decision to carry out concurrent validation must be justified, docu-mented and approved by authorised personnel.

30 Documentation requirements for concurrent validation are the same asspecified for prospective validation.


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Retrospective validation

31 Retrospective validation is only acceptable for well-established processesand will be inappropriate where there have been recent changes in thecomposition of the product, operating procedures or equipment.

32 Validation of such processes should be based on historical data. The stepsinvolved require the preparation of a specific protocol and the reportingof the results of the data review, leading to a conclusion and a recom-mendation.

33 The source of data for this validation should include, but not be lim-ited to batch processing and packaging records, process control charts,maintenance log books, records of personnel changes, process capabilitystudies, finished product data, including trend cards and storage stabilityresults.

34 Batches selected for retrospective validation should be representative of allbatches made during the review period, including any batches that failedto meet specifications, and should be sufficient in number to demonstrateprocess consistency. Additional testing of retained samples may be neededto obtain the necessary amount or type of data to retrospectively validatethe process.

35 For retrospective validation, generally data from ten to thirty consecutivebatches should be examined to assess process consistency, but fewer batchesmay be examined if justified.

Cleaning Validation

36 Cleaning validation should be performed in order to confirm the effective-ness of a cleaning procedure. The rationale for selecting limits of carry overof product residues, cleaning agents and microbial contamination shouldbe logically based on the materials involved. The limits should be achiev-able and verifiable.

37 Validated analytical methods having sensitivity to detect residues or con-taminants should be used. The detection limit for each analytical methodshould be sufficiently sensitive to detect the established acceptable level ofthe residue or contaminant.

38 Normally only cleaning procedures for product contact surfaces of theequipment need to be validated. Consideration should be given to non-contact parts. The intervals between use and cleaning as well as cleaning


and reuse should be validated. Cleaning intervals and methods should bedetermined.

39 For cleaning procedures for products and processes which are similar, it isconsidered acceptable to select a representative range of similar productsand processes. A single validation study utilising a “worst case” approachcan be carried out which takes account of the critical issues.

40 Typically three consecutive applications of the cleaning procedure shouldbe performed and shown to be successful in order to prove that the methodis validated.

41 “Test until clean” is not considered an appropriate alternative to cleaningvalidation.

42 Products which simulate the physicochemical properties of the substancesto be removed may exceptionally be used instead of the substances them-selves, where such substances are either toxic or hazardous.

Change Control

43 Written procedures should be in place to describe the actions to be takenif a change is proposed to a starting material, product component, processequipment, process environment (or site), method of production or testingor any other change that may affect product quality or reproducibilityof the process. Change control procedures should ensure that sufficientsupporting data are generated to demonstrate that the revised process willresult in a product of the desired quality, consistent with the approvedspecifications.

44 All changes that may affect product quality or reproducibility of the processshould be formally requested, documented and accepted. The likely impactof the change of facilities, systems and equipment on the product shouldbe evaluated, including risk analysis. The need for, and the extent of, re-qualification and re-validation should be determined.

Revalidation

45 Facilities, systems, equipment and processes, including cleaning, should beperiodically evaluated to confirm that they remain valid. Where no signif-icant changes have been made to the validated status, a review with evi-dence that facilities, systems, equipment and processes meet the prescribedrequirements fulfils the need for revalidation.


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Glossary

Definitions of terms relating to qualification and validation which are notgiven in the glossary of the current EC Guide to GMP, but which are usedin this Annex, are given below.

Change controlA formal system by which qualified representatives of appropriate disci-plines review proposed or actual changes that might affect the validatedstatus of facilities, systems, equipment or processes. The intent is to deter-mine the need for action that would ensure and document that the systemis maintained in a validated state.

Cleaning validationCleaning validation is documented evidence that an approved cleaning pro-cedure will provide equipment which is suitable for processing medicinalproducts.

Concurrent validationValidation carried out during routine production of products intended forsale.

Design qualification (DQ)The documented verification that the proposed design of the facilities, sys-tems and equipment is suitable for the intended purpose.

Installation qualification (IQ)The documented verification that the facilities, systems and equipment, asinstalled or modified, comply with the approved design and the manufac-turer’s recommendations.

Operational qualification (OQ)The documented verification that the facilities, systems and equipment,as installed or modified, perform as intended throughout the anticipatedoperating ranges.

Performance qualification (PQ)The documented verification that the facilities, systems and equipment, asconnected together, can perform effectively and reproducibly, based on theapproved process method and product specification.

Process validationThe documented evidence that the process, operated within establishedparameters, can perform effectively and reproducibly to produce a medici-nal product meeting its predetermined specifications and quality attributes.


Prospective validationValidation carried out before routine production of products intended forsale.

Retrospective validationValidation of a process for a product which has been marketed based uponaccumulated manufacturing, testing and control batch data.

Re-validationA repeat of the process validation to provide an assurance that changes inthe process/equipment introduced in accordance with change control pro-cedures do not adversely affect process characteristics and product quality.

Risk analysisMethod to assess and characterise the critical parameters in the function-ality of an equipment or process.

Simulated productA material that closely approximates the physical and, where practical, thechemical characteristics (e.g. viscosity, particle size, pH, etc.) of the productunder validation. In many cases, these characteristics may be satisfied by aplacebo product batch.

SystemA group of equipment with a common purpose.

Worst caseA condition or set of conditions encompassing upper and lower processinglimits and circumstances, within standard operating procedures which posethe greatest chance of product or process failure when compared to idealconditions. Such conditions do not necessarily induce product or processfailure.


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ANNEX 16 CERTIFICATION BY A QUALIFIED PERSON ANDBATCH RELEASE

1 Scope

1.1 This annex to the Guide to Good Manufacturing Practice for MedicinalProducts (“the Guide”) gives guidance on the certification by a QualifiedPerson (Q.P.) and batch release within the European Community (EC) orEuropean Economic Area (EEA) of medicinal products holding a marketingauthorisation or made for export. The relevant legislative requirements arecontained in Article 51 of Directive 2001/83/EC or Article 55 of Directive2001/82/EC.

1.2 The annex covers in particular those cases where a batch has had differ-ent stages of production or testing conducted at different locations or bydifferent manufacturers, and where an intermediate or bulk productionbatch is divided into more than one finished product batch. It also coversthe release of batches which have been imported to the EC/EEA both whenthere is and is not a mutual recognition agreement between the Communityand the third country. The guidance may also be applied to investigationalmedicinal products, subject to any difference in the legal provisions andmore specific guidance in Annex 13 to the Guide.

1.3 This annex does not, of course, describe all possible arrangements whichare legally acceptable. Neither does it address the official control authoritybatch release which may be specified for certain blood and immunologicalproducts in accordance with Article 11 point 5.4 and Articles 1091 and110 of Directive 2001/83/EC.

1.4 The basic arrangements for batch release for a product are defined byits Marketing Authorisation. Nothing in this annex should be taken asoverriding those arrangements.

2 Principle

2.1 Each batch of finished product must be certified by a Q.P. within theEC/EEA before being released for sale or supply in the EC/EEA or forexport.

1 As amended by Directive 2002/98/EC of the European Parliament and of theCouncil of 27 January 2003 setting standards of quality and safety for the col-lection, testing, processing, storage and distribution of human blood and bloodcomponents and amending Directive 2001/83/EC (OJ L 33, 8.2.2003, p. 30).


2.2 The purpose of controlling batch release in this way is:

� to ensure that the batch has been manufactured and checked in accor-dance with the requirements of its marketing authorisation, the prin-ciples and guidelines of EC Good Manufacturing Practice or the goodmanufacturing practice of a third country recognised as equivalent undera mutual recognition agreement and any other relevant legal requirementbefore it is placed on the market, and

� in the event that a defect needs to be investigated or a batch recalled, toensure that the Q.P. who certified the batch and the relevant records arereadily identifiable.

3 Introduction

3.1 Manufacture, including quality control testing, of a batch of medicinalproducts takes place in stages which may be conducted at different sites andby different manufacturers. Each stage should be conducted in accordancewith the relevant marketing authorisation, Good Manufacturing Practiceand the laws of the Member State concerned and should be taken intoaccount by the Q.P. who certifies the finished product batch before releaseto the market.

3.2 However in an industrial situation it is usually not possible for a singleQ.P. to be closely involved with every stage of manufacture. The Q.P. whocertifies a finished product batch may need therefore to rely in part onthe advice and decisions of others. Before doing so he should ensure thatthis reliance is well founded, either from personal knowledge or fromthe confirmation by other Q.P.s within a quality system which he hasaccepted.

3.3 When some stages of manufacture occur in a third country it is still arequirement that production and testing are in accordance with the mar-keting authorisation, that the manufacturer is authorised according to thelaws of the country concerned and that manufacture follows good manu-facturing practices at least equivalent to those of the EC.

3.4 Certain words used in this annex have particular meanings attributed tothem, as defined in the glossary [to Annex 16].

4 General

4.1 One batch of finished product may have different stages of manufac-ture, importation, testing and storage before release conducted at differ-ent sites. Each site should be approved under one or more manufacturing


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authorisations and should have at its disposal the services of at least oneQ.P. However the correct manufacture of a particular batch of product,regardless of how many sites are involved, should be the overall concernof the Q.P. who certifies that finished product batch before release.

4.2 Different batches of a product may be manufactured or imported andreleased at different sites in the EC/EEA. For example a Community mar-keting authorisation may name batch release sites in more than one memberstate, and a national authorisation may also name more than one releasesite. In this situation the holder of the marketing authorisation and eachsite authorised to release batches of the product should be able to identifythe site at which any particular batch has been released and the Q.P. whowas responsible for certifying that batch.

4.3 The Q.P. who certifies a finished product batch before release may doso based on his personal knowledge of all the facilities and proceduresemployed, the expertise of the persons concerned and of the quality systemwithin which they operate. Alternatively he may rely on the confirmationby one or more other Q.P.s of the compliance of intermediate stages ofmanufacture within a quality system which he has accepted.

This confirmation by other Q.P.s should be documented and should iden-tify clearly the matters which have been confirmed. The systematic arrange-ments to achieve this should be defined in a written agreement.

4.4 The agreement mentioned above is required whenever a Q.P. wishes to relyon the confirmation by another Q.P. The agreement should be in generalaccordance with Chapter 7 of the Guide. The Q.P. who certifies the finishedproduct batch should ensure the arrangements in the agreement are verified.The form of such an agreement should be appropriate to the relationshipbetween the parties; for example a standard operating procedure within acompany or a formal contract between different companies even if withinthe same group.

4.5 The agreement should include an obligation on the part of the providerof a bulk or intermediate product to notify the recipient(s) of any devi-ations, out-of-specification results, non-compliance with GMP, investiga-tions, complaints or other matters which should be taken into accountby the Q.P. who is responsible for certifying the finished productbatch.

4.6 When a computerised system is used for recording certification and batchrelease, particular note should be taken of the guidance in Annex 11 to thisGuide.

4.7 Certification of a finished product batch against a relevant marketingauthorisation by a Q.P. in the EC/EEA need not be repeated on the samebatch provided the batch has remained within the EC/EEA.


4.8 Whatever particular arrangements are made for certification and release ofbatches, it should always be possible to identify and recall without delayall products which could be rendered hazardous by a quality defect in thebatch.

5 Batch Testing and Release of Products Manufacturedin EC/EEA

5.1 When all manufacture occurs at a single authorised site.When all production and control stages are carried out at a single site,the conduct of certain checks and controls may be delegated to othersbut the Q.P. at this site who certifies the finished product batch normallyretains personal responsibility for these within a defined quality system.However he may, alternatively, take account of the confirmation of theintermediate stages by other Q.Ps on the site who are responsible for thosestages.

5.2 Different stages of manufacture are conducted at different sites within thesame company.When different stages of the manufacture of a batch are carried out at dif-ferent sites within the same company (which may or may not be coveredby the same manufacturing authorisation) a Q.P. should be responsible foreach stage. Certification of the finished product batch should be performedby a Q.P. of the manufacturing authorisation holder responsible for releas-ing the batch to the market, who may take personal responsibility for allstages or may take account of the confirmation of the earlier stages by therelevant Q.P.s responsible for those stages.

5.3 Some intermediate stages of manufacture are contracted to a differentcompany.One or more intermediate production and control stages may be contractedto a holder of a manufacturing authorisation in another company. A Q.P.of the contract giver may take account of the confirmation of the relevantstage by a Q.P. of the contract acceptor but is responsible for ensuringthat this work is conducted within the terms of a written agreement. Thefinished product batch should be certified by a Q.P. of the manufacturingauthorisation holder responsible for releasing the batch to the market.

5.4 A bulk production batch is assembled at different sites into several finishedproduct batches which are released under a single marketing authorisation.This could occur, for example, under a national marketing authorisationwhen the assembly sites are all within one member state or under a Commu-nity marketing authorisation when the sites are in more than one memberstate.


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5.4.1 One alternative is for a Q.P. of the manufacturing authorisationholder making the bulk production batch to certify all the finishedproduct batches before release to the market. In doing so he mayeither take personal responsibility for all manufacturing stages ortake account of the confirmation of assembly by the Q.P.s of theassembly sites.

5.4.2 Another alternative is for the certification of each finished productbatch before release to the market to be performed by a Q.P of themanufacturer who has conducted the final assembly operation. Indoing so he may either take personal responsibility for all manu-facturing stages or take account of the confirmation of the bulk pro-duction batch by a Q.P. of the manufacturer of the bulk batch.

5.4.3 In all cases of assembly at different sites under a single market-ing authorisation, there should be one person, normally a Q.P. ofthe manufacturer of the bulk production batch, who has an over-all responsibility for all released finished product batches which arederived from one bulk production batch. The duty of this personis to be aware of any quality problems reported on any of the fin-ished product batches and to co-ordinate any necessary action arisingfrom a problem with the bulk batch. While the batch numbers of thebulk and finished product batches are not necessarily the same, thereshould be a documented link between the two numbers so that anaudit trail can be established.

5.5 A bulk production batch is assembled at different sites into several finishedproduct batches which are released under different marketing authorisa-tions. This could occur, for example, when a multi-national organisationholds national marketing authorisations for a product in several memberstates or when a generic manufacturer purchases bulk products and assem-bles and releases them for sale under his own marketing authorisation.

5.5.1 A Q.P. of the manufacturer doing the assembly who certifies thefinished product batch may either take personal responsibility for allmanufacturing stages or may take account of the confirmation of thebulk production batch by a Q.P. of the bulk product manufacturer.

5.5.2 Any problem identified in any of the finished product batches whichmay have arisen in the bulk production batch should be commu-nicated to the Q.P. responsible for confirming the bulk productionbatch, who should then take any necessary action in respect of all fin-ished product batches produced from the suspected bulk productionbatch. This arrangement should be defined in a written agreement.

5.6 A finished product batch is purchased and released to the market by amanufacturing authorisation holder in accordance with his own marketingauthorisation. This could occur, for example, when a company supplying


generic products holds a marketing authorisation for products made byanother company, purchases finished products which have not been certi-fied against his marketing authorisation and releases them under his ownmanufacturing authorisation in accordance with his own marketing autho-risation.In this situation a Q.P. of the purchaser should certify the finished productbatch before release. In doing so he may either take personal responsibilityfor all manufacturing stages or may take account of the confirmation ofthe batch by a Q.P. of the vendor manufacturer.

5.7 The quality control laboratory and the production site are authorised underdifferent manufacturing authorisations.A Q.P. certifying a finished product batch may either take personal respon-sibility for the laboratory testing or may take account of the confirmationby another Q.P. of the testing and results. The other laboratory and Q.P.need not be in the same member state as the manufacturing authorisationholder releasing the batch. In the absence of such confirmation the Q.P.should himself have personal knowledge of the laboratory and its proce-dures relevant to the finished product to be certified.

6 Batch Testing and Release of Products Imported froma Third Country

6.1 General

6.1.1 Importation of finished products should be conducted by an importeras defined in the glossary to this annex.

6.1.2 Each batch of imported finished product should be certified by a Q.P.of the importer before release for sale in the EC/EEA.

6.1.3 Unless a mutual recognition agreement is in operation between theCommunity and the third country (see Section 7 [of Annex 16]),samples from each batch should be tested in the EC/EEA beforecertification of the finished product batch by a Q.P. Importation andtesting need not necessarily be performed in the same member state.

6.1.4 The guidance in this section should also be applied as appropriate tothe importation of partially manufactured products.

6.2 A complete batch or the first part of a batch of a medicinal product isimported.The batch or part batch should be certified by a Q.P of the importer beforerelease. This Q.P. may take account of the confirmation of the checking,sampling or testing of the imported batch by a Q.P. of another manufac-turing authorisation holder (i.e. within EC/EEA).


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6.3 Part of a finished product batch is imported after another part of the samebatch has previously been imported to the same or a different site.

6.3.1 A Q.P. of the importer receiving a subsequent part of the batch maytake account of the testing and certification by a Q.P. of the first partof the batch. If this is done, the Q.P. should ensure, based on evidence,that the two parts do indeed come from the same batch, that thesubsequent part has been transported under the same conditions asthe first part and that the samples that were tested are representativeof the whole batch.

6.3.2 The conditions in paragraph 6.3.1 is most likely to be met when themanufacturer in the third country and the importer(s) in the EC/EEAbelong to the same organisation operating under a corporate systemof quality assurance. If the Q.P. cannot ensure that the conditions inparagraph 6.3.1 are met, each part of the batch should be treated asa separate batch.

6.3.3 When different parts of the batch are released under the same mar-keting authorisation, one person, normally a Q.P. of the importerof the first part of a batch, should take overall responsibility forensuring that records are kept of the importation of all parts of thebatch and that the distribution of all parts of the batch is traceablewithin the EC/EEA. He should be made aware of any quality prob-lems reported on any part of the batch and should co-ordinate anynecessary action concerning these problems and their resolution.

This should be ensured by a written agreement between all theimporters concerned.

6.4 Location of sampling for testing in EC/EEA.

6.4.1 Samples should be representative of the batch and be tested in theEC/EEA. In order to represent the batch it may be preferable to takesome samples during processing in the third country. For example,samples for sterility testing may best be taken throughout the fillingoperation. However in order to represent the batch after storage andtransportation some samples should also be taken after receipt of thebatch in the EC/EEA.

6.4.2 When any samples are taken in a third country, they should either beshipped with and under the same conditions as the batch which theyrepresent, or if sent separately it should be demonstrated that thesamples are still representative of the batch, for example by definingand monitoring the conditions of storage and shipment. When theQ.P. wishes to rely on testing of samples taken in a third country,this should be justified on technical grounds.


7 Batch Testing and Release of Products Imported from a ThirdCountry with which the EC has a Mutual RecognitionAgreement (MRA)

7.1 Unless otherwise specified in the agreement, an MRA does not removethe requirement for a Q.P. within the EC/EEA to certify a batch beforeit is released for sale or supply within the EC/EEA. However, subject todetails of the particular agreement, the Q.P. of the importer may rely onthe manufacturer’s confirmation that the batch has been made and testedin accordance with its marketing authorisation and the GMP of the thirdcountry and need not repeat the full testing. The Q.P. may certify the batchfor release when he is satisfied with this confirmation and that the batch hasbeen transported under the required conditions and has been received andstored in the EC/EEA by an importer as defined in Section 8 [Annex 16].

7.2 Other procedures, including those for receipt and certification of partbatches at different times and/or at different sites, should be the same asin Section 6 [Annex 16].

8 Routine Duties of a Qualified Person

8.1 Before certifying a batch prior to release the Q.P. doing so should ensure,with reference to the guidance above, that at least the following require-ments have been met:

(a) the batch and its manufacture comply with the provisions of the market-ing authorisation (including the authorisation required for importationwhere relevant);

(b) manufacture has been carried out in accordance with Good Manufac-turing Practice or, in the case of a batch imported from a third coun-try, in accordance with good manufacturing practice standards at leastequivalent to EC GMP;

(c) the principal manufacturing and testing processes have been validated;account has been taken of the actual production conditions and man-ufacturing records;

(d) any deviations or planned changes in production or quality controlhave been authorised by the persons responsible in accordance with adefined system. Any changes requiring variation to the marketing ormanufacturing authorisation have been notified to and authorised bythe relevant authority;

(e) all the necessary checks and tests have been performed, including anyadditional sampling, inspection, tests or checks initiated because ofdeviations or planned changes;


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(f) all necessary production and quality control documentation has beencompleted and endorsed by the staff authorised to do so;

(g) all audits have been carried out as required by the quality assurancesystem;

(h) the QP should in addition take into account any other factors of whichhe is aware which are relevant to the quality of the batch.

A Q.P. may have additional duties in accordance with national legislationor administrative procedures.

8.2 A Q.P. who confirms the compliance of an intermediate stage of manufac-ture, as described in paragraph 4.3, has the same obligations as above inrelation to that stage unless specified otherwise in the agreement betweenthe Q.P.s.

8.3 A Q.P. should maintain his knowledge and experience up to date in the lightof technical and scientific progress and changes in quality managementrelevant to the products which he is required to certify.

8.4 If a Q.P. is called upon to certify a batch of a product type with which heis unfamiliar, for example because the manufacturer for whom he worksintroduces a new product range or because he starts to work for a differ-ent manufacturer, he should first ensure that he has gained the relevantknowledge and experience necessary to fulfil this duty.

In accordance with national requirements the Q.P. may be required tonotify the authorities of such a change and may be subject to renewedauthorisation.

9 Glossary

Certain words and phrases in this annex are used with the particular mean-ings defined below. Reference should also be made to the Glossary in themain part of the Guide.

Bulk production batchA batch of product, of a size described in the application for a marketingauthorisation, either ready for assembly into final containers or in individ-ual containers ready for assembly to final packs. (A bulk production batchmay, for example, consist of a bulk quantity of liquid product, of soliddosage forms such as tablets or capsules, or of filled ampoules).

Certification of the finished product batchThe certification in a register or equivalent document by a Q.P., as defined inArticle 51 of Directive 2001/83/EC and Article 55 of Directive 2001/82/EC,before a batch is released for sale or distribution.


ConfirmationA signed statement that a process or test has been conducted in accordancewith GMP and the relevant marketing authorisation, as agreed in writingwith the Q.P. responsible for certifying the finished product batch beforerelease. Confirm and confirmed have equivalent meanings.

Finished product batchWith reference to the control of the finished product, a finished productbatch is defined in Part 1 Module 3 point 3.2.2.5 of Directive 2001/83/EC2

and in Part 2 Section F 1 of Directive 2001/82/EC. In the context of thisannex the term in particular denotes the batch of product in its final packfor release to the market.

ImporterThe holder of the authorisation required by Article 40.3 of Directive2001/83/EC and Article 44.3 of Directive 2001/82/EC for importing medi-cinal products from third countries.

Mutual Recognition Agreement (MRA)The “appropriate arrangement” between the Community and an export-ing third country mentioned in Article 51(2) of Directive 2001/83/EC andArticle 55(2) of Directive 2001/82/EC.

Qualified Person (Q.P.)The person defined in Article 48 of Directive 2001/83/EC and Article 52of Directive 2001/82/EC.

2 Amended by Commission Directive 2003/63/EC of 25 June 2003 amendingDirective 2001/83/EC of the European Parliament and of the Council on theCommunity code relating to medicinal products for human use (OJ L 159,27.06.2003, p.46).


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ANNEX 17 PARAMETRIC RELEASE

1 Principle

1.1 The definition of Parametric Release used in this Annex is based onthat proposed by the European Organization for Quality: “A system ofrelease that gives the assurance that the product is of the intended qual-ity based on information collected during the manufacturing process andon the compliance with specific GMP requirements related to ParametricRelease”.

1.2 Parametric release should comply with the basic requirements of GMP,with applicable annexes and the following guidelines.

2 Parametric Release

2.1 It is recognised that a comprehensive set of in-process tests and controlsmay provide greater assurance of the finished product meeting specificationthan finished product testing.

2.2 Parametric release may be authorised for certain specific parameters asan alternative to routine testing of finished products. Authorisation forparametric release should be given, refused or withdrawn jointly by thoseresponsible for assessing products together with the GMP inspectors.

3 Parametric Release for Sterile Products

3.1 This section is only concerned with that part of Parametric Release whichdeals with the routine release of finished products without carrying out asterility test. Elimination of the sterility test is only valid on the basis ofsuccessful demonstration that predetermined, validated sterilising condi-tions have been achieved.

3.2 A sterility test only provides an opportunity to detect a major failure of thesterility assurance system due to statistical limitations of the method.

3.3 Parametric Release can be authorised if the data demonstrating correctprocessing of the batch provides sufficient assurance, on its own, that theprocess designed and validated to ensure the sterility of the product hasbeen delivered.

3.4 At present Parametric release can only be approved for products terminallysterilized in their final container.


3.5 Sterilization methods according to European Pharmacopoeia requirementsusing steam, dry heat and ionising radiation may be considered for para-metric release.

3.6 It is unlikely that a completely new product would be considered as suitablefor Parametric Release because a period of satisfactory sterility test resultswill form part of the acceptance criteria. There may be cases when a newproduct is only a minor variation, from the sterility assurance point of view,and existing sterility test data from other products could be considered asrelevant.

3.7 A risk analysis of the sterility assurance system focused on an evaluationof releasing non-sterilised products should be performed.

3.8 The manufacturer should have a history of good compliance with GMP.

3.9 The history of non-sterility of products and of results of sterility testscarried out on the product in question together with products processedthrough the same or a similar sterility assurance system should be takeninto consideration when evaluating GMP compliance.

3.10 A qualified experienced sterility assurance engineer and a qualified micro-biologist should normally be present on the site of production and steril-ization.

3.11 The design and original validation of the product should ensure thatintegrity can be maintained under all relevant conditions.

3.12 The change control system should require review of change by sterilityassurance personnel.

3.13 There should be a system to control microbiological contamination in theproduct before sterilisation.

3.14 There should be no possibility for mix ups between sterilised and non-sterilised products. Physical barriers or validated electronic systems mayprovide such assurance.

3.15 The sterilization records should be checked for compliance to specificationby at least two independent systems. These systems may consist of twopeople or a validated computer system plus a person.

3.16 The following additional items should be confirmed prior to release of eachbatch of product.

� All planned maintenance and routine checks have been completed in thesterilizer used.

� All repairs and modifications have been approved by the sterility assur-ance engineer and microbiologist.

� All instrumentation was in calibration.� The sterilizer had a current validation for the product load processed.


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3.17 Once parametric release has been granted, decisions for release or rejectionof a batch should be based on the approved specifications. Non-compliancewith the specification for parametric release cannot be overruled by a passof a sterility test.

4 Glossary

Parametric ReleaseA system of release that gives the assurance that the product is of theintended quality based on information collected during the manufacturingprocess and on the compliance with specific GMP requirements related toParametric Release.

Sterility Assurance SystemThe sum total of the arrangements made to assure the sterility of prod-ucts. For terminally sterilized products these typically include the followingstages:

(a) Product design.(b) Knowledge of and, if possible, control of the microbiological condition

of starting materials and process aids (e.g. gases and lubricants).(c) Control of the contamination of the process of manufacture to avoid the

ingress of microorganisms and their multiplication in the product. Thisis usually accomplished by cleaning and sanitization of product con-tact surfaces, prevention of aerial contamination by handling in cleanrooms, use of process control time limits and, if applicable, filtrationstages.

(d) Prevention of mix up between sterile and non-sterile product streams.(e) Maintenance of product integrity.(f) The sterilization process.(g) The totality of the Quality System that contains the Sterility Assur-

ance System, e.g. change control, training, written procedures, releasechecks, planned preventative maintenance, failure mode analysis, pre-vention of human error, validation calibration, etc.


ANNEX 18 GOOD MANUFACTURING PRACTICE FOR ACTIVEPHARMACEUTICAL INGREDIENTS

Editor’snote

Requirements for active substances used as starting materials from October2005 are now covered in Part II.


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ANNEX 19 REFERENCE AND RETENTION SAMPLES

Editor’snote

Came into operation 1 June 2006.

1 Scope

1.1 This Annex to the Guide to Good Manufacturing Practice for MedicinalProducts (“the GMP Guide”) gives guidance on the taking and holdingof reference samples of starting materials, packaging materials or finishedproducts and retention samples of finished products.

1.2 Specific requirements for investigational medicinal products are given inAnnex 13 to the Guide.

1.3 This annex also includes guidance on the taking of retention samples forparallel imported/ distributed medicinal products.

2 Principle

2.1 Samples are retained to fulfil two purposes; firstly to provide a sample foranalytical testing and secondly to provide a specimen of the fully finishedproduct. Samples may therefore fall into two categories:

Reference sample: a sample of a batch of starting material, packaging ma-terial or finished product which is stored for the purpose of beinganalysed should the need arise during the shelf life of the batchconcerned. Where stability permits, reference samples from criticalintermediate stages (e.g. those requiring analytical testing and release)or intermediates, that are transported outside of the manufacturer’scontrol, should be kept.

Retention sample: a sample of a fully packaged unit from a batch offinished product. It is stored for identification purposes. For example,presentation, packaging, labelling, patient information leaflet, batchnumber, expiry date should the need arise during the shelf life of thebatch concerned. There may be exceptional circumstances where thisrequirement can be met without retention of duplicate samples e.g.where small amounts of a batch are packaged for different markets orin the production of very expensive medicinal products.

For finished products, in many instances the reference and retentionsamples will be presented identically, i.e. as fully packaged units. In such


circumstances, reference and retention samples may be regarded as inter-changeable.

2.2 It is necessary for the manufacturer, importer or site of batch release, asspecified under Sections 7 and 8, to keep reference and/or retention samplesfrom each batch of finished product and, for the manufacturer to keepa reference sample from a batch of starting material (subject to certainexceptions – see Section 3.2 below) and/or intermediate product. Eachpackaging site should keep reference samples of each batch of primaryand printed packaging materials. Availability of printed materials as partof the reference and/or retention sample of the finished product can beaccepted.

2.3 The reference and/or retention samples serve as a record of the batch offinished product or starting material and can be assessed in the event of,for example, a dosage form quality complaint, a query relating to compli-ance with the marketing authorisation, a labelling/packaging query or apharmacovigilance report.

2.4 Records of traceability of samples should be maintained and be availablefor review by competent authorities.

3 Duration of Storage

3.1 Reference and retention samples from each batch of finished productshould be retained for at least one year after the expiry date. The ref-erence sample should be contained in its finished primary packaging orin packaging composed of the same material as the primary container inwhich the produce is marketed (for veterinary medicinal products otherthan immunologicals, see also Annex 4, paragraphs 8 & 9).

3.2 Unless a longer period is required under the law of the Member Stateof manufacture, samples of starting materials (other than solvents, gasesor water used in the manufacturing process) shall be retained for at leasttwo years after the release of product. That period may be shortened if theperiod of stability of the material, as indicated in the relevant specification,is shorter. Packaging materials should be retained for the duration of theshelf life of the finished product concerned.

4 Size of Reference and Retention Samples

4.1 The reference sample should be of sufficient size to permit the carrying out,on, at least, two occasions, of the full analytical controls on the batch in


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accordance with the Marketing Authorisation File which has been assessedand approved by the relevant Competent Authority/Authorities. Where itis necessary to do so, unopened packs should be used when carrying outeach set of analytical controls. Any proposed exception to this should bejustified to, and agreed with, the relevant competent authority.

4.2 Where applicable, national requirements relating to the size of referencesamples and, if necessary, retention samples, should be followed.

4.3 Reference samples should be representative of the batch of starting mate-rial, intermediate product or finished product from which they are taken.Other samples may also be taken to monitor the most stressed part of aprocess (e.g. beginning or end of a process). Where a batch is packaged intwo, or more, distinct packaging operations, at least one retention sampleshould be taken from each individual packaging operation. Any proposedexception to this should be justified to, and agreed with, the relevant com-petent authority.

4.4 It should be ensured that all necessary analytical materials and equipmentare still available, or are readily obtainable, in order to carry out all testsgiven in the specification until one year after expiry of the last batch manu-factured.

5 Storage Conditions

5.1 Storage of reference samples of finished products and active substancesshould be in accordance with the current version of the Note for Guidanceon Declaration of Storage Conditions for Medicinal Products and ActiveSubstances.

5.2 Storage conditions should be in accordance with the marketing authorisa-tion (e.g. refrigerated storage where relevant).

6 Written Agreements

6.1 Where the marketing authorisation holder is not the same legal entity asthe site(s) responsible for batch release within the EEA, the responsibilityfor taking and storage of reference/retention samples should be defined ina written agreement between the two parties in accordance with Chap-ter 7 of the EC Guide to Good Manufacturing Practice. This applies alsowhere any manufacturing or batch release activity is carried out at a siteother than that with overall responsibility for the batch on the EEA mar-ket and the arrangements between each different site for the taking and


keeping of reference and retention samples should be defined in a writtenagreement.

6.2 The Qualified Person who certifies a batch for sale should ensure thatall relevant reference and retention samples are accessible at all reasonabletimes. Where necessary, the arrangements for such access should be definedin a written agreement.

6.3 Where more than one site is involved in the manufacture of a finishedproduct, the availability of written agreements is key to controlling thetaking and location of reference and retention samples.

7 Reference Samples – General Points

7.1 Reference samples are for the purpose of analysis and, therefore, shouldbe conveniently available to a laboratory with validated methodology. Forstarting materials used for medicinal products manufactured within theEEA, this is the original site of manufacture of the finished product. Forfinished products manufactured within the EEA, this is the original site ofmanufacture.

7.2 For finished products manufactured by a manufacturer in a country outsidethe EEA;

7.2.1 where an operational Mutual Recognition Agreement (MRA) is inplace, the reference sample may be taken and stored at the site ofmanufacture. This should be covered in a written agreement (asreferred to in Section 6 above) between the importer/site of batchrelease and the manufacturer located outside the EEA.

7.2.2 where an operational MRA is not in place, reference samples of thefinished medicinal product should be taken and stored at an autho-rised manufacturer located within the EEA. These samples shouldbe taken in accordance with written agreement(s) between all of theparties concerned. The samples should, preferably, be stored at thelocation where testing on importation has been performed.

7.2.3 reference samples of starting materials and packaging materialsshould be kept at the original site at which they were used in themanufacture of the medicinal product.

8 Retention Samples – General Points

8.1 A retention sample should represent a batch of finished products as dis-tributed in the EEA and may need to be examined in order to confirm non-technical attributes for compliance with the marketing authorisation or


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EU legislation. Therefore, retention samples should in all cases be locatedwithin the EEA. These should preferably be stored at the site where theQualified Person (Q.P.) certifying the finished product batch is located.

8.2 In accordance with Section 8.1 above, where an operational MRA is inplace and reference samples are retained at a manufacturer located in acountry outside the EEA (Section 7.2.2 above), separate retention samplesshould be kept within the EEA.

8.3 Retention samples should be stored at the premises of an authorised man-ufacturer in order to permit ready access by the Competent Authority.

8.4 Where more than one manufacturing site within the EEA is involved inthe manufacture importation/packaging/testing/batch release, as appropri-ate of a product, the responsibility for taking and storage of retentionsamples should be defined in a written agreement(s) between the partiesconcerned.

9 Reference and Retention Samples for ParallelImported/Parallel Distributed Products.

9.1 Where the secondary packaging is not opened, only the packaging materialused needs to be retained, as there is no, or little, risk of product mixup.

9.2 Where the secondary packaging is opened, for example, to replace thecarton or patient information leaflet, then one retention sample, per pack-aging operation, containing the product should be taken, as there is a riskof product mix-up during the assembly process. It is important to be ableto identify quickly who is responsible in the event of a mix-up (originalmanufacturer or parallel import assembler), as it would affect the extentof any resulting recall.

10 Reference and Retention Samples in the Case of Closedownof a Manufacturer

10.1 Where a manufacturer closes down and the manufacturing authorisation issurrendered, revoked, or ceases to exist, it is probable that many unexpiredbatches of medicinal products manufactured by that manufacturer remainon the market. In order for those batches to remain on the market, themanufacturer should make detailed arrangements for transfer of referenceand retention samples (and relevant GMP documentation) to an authorisedstorage site. The manufacturer should satisfy the Competent Authority thatthe arrangements for storage are satisfactory and that the samples can, ifnecessary, be readily accessed and analysed.


10.2 If the manufacturer is not in a position to make the necessary arrangementsthis may be delegated to another manufacturer. The Marketing Authorisa-tion holder (MAH) is responsible for such delegation and for the provisionof all necessary information to the Competent Authority. In addition, theMAH should, in relation to the suitability of the proposed arrangementsfor storage of reference and retention samples, consult with the competentauthority of each Member State in which any unexpired batch has beenplaced on the market.

10.3 These requirements apply also in the event of the closedown of a manu-facture located outside the EEA. In such instances, the importer has aparticular responsibility to ensure that satisfactory arrangements are putin place and that the competent authority/authorities is/are consulted.


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GLOSSARY OF TERMS USED IN THE EU GUIDE TO GMP

Note: Definitions given below apply to the words as used in this guide.They may have different meanings in other contexts.

AIR-LOCKAn enclosed space with two or more doors, and which is interposedbetween two or more rooms, e.g. of differing class of cleanliness, for thepurpose of controlling the air-flow between those rooms when they need tobe entered. An air-lock is designed for and used by either people or goods.

BATCH (OR LOT)A defined quantity of starting material, packaging material or productprocessed in one process or series of processes so that it could be expectedto be homogeneous.

Note: To complete certain stages of manufacture, it may be necessaryto divide a batch into a number of sub-batches, which are later broughttogether to form a final homogeneous batch. In the case of continuousmanufacture, the batch must correspond to a defined fraction of the pro-duction, characterised by its intended homogeneity.

For control of the finished product, the following definition has beengiven in Annex 1 of Directive 2001/83/EC as amended by Directive 2003/63/EC (see http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev1.htm): “For the control of the finished product, a batch of aproprietary medicinal product comprises all the units of a pharmaceuticalform which are made from the same initial mass of material and haveundergone a single series of manufacturing operations or a single sterilisa-tion operation or, in the case of a continuous production process, all theunits manufactured in a given period of time.”

BATCH NUMBER (OR LOT NUMBER)A distinctive combination of numbers and/or letters which specifically iden-tifies a batch.

BIOGENERATORA contained system, such as a fermenter, into which biological agents areintroduced along with other materials so as to effect their multiplicationor their production of other substances by reaction with the other materi-als. Biogenerators are generally fitted with devices for regulation, control,connection, material addition and material withdrawal.

BIOLOGICAL AGENTSMicro-organisms, including genetically engineered micro-organisms, cellcultures and endoparasites, whether pathogenic or not.


BULK PRODUCTAny product which has completed all processing stages up to, but notincluding, final packaging.

CALIBRATIONThe set of operations which establish, under specified conditions, the rela-tionship between values indicated by a measuring instrument or measuringsystem, or values represented by a material measure, and the correspondingknown values of a reference standard.

CELL BANKCell bank system: A cell bank system is a system whereby successive batchesof a product are manufactured by culture in cells derived from the samemaster cell bank. A number of containers from the master cell bank areused to prepare a working cell bank. The cell bank system is validated fora passage level or number of population doublings beyond that achievedduring routine production.

Master cell bank: A culture of [fully characterised] cells distributed intocontainers in a single operation, processed together in such a manner asto ensure uniformity and stored in such a manner as to ensure stability. Amaster cell bank is usually stored at −70◦C or lower.

Working cell bank: A culture of cells derived from the master cell bankand intended for use in the preparation of production cell cultures. Theworking cell bank is usually stored at −70◦C or lower.

CELL CULTUREThe result from the in-vitro growth of cells isolated from multicellularorganisms.

CLEAN AREAAn area with defined environmental control of particulate and microbialcontamination, constructed and used in such a way as to reduce the intro-duction, generation and retention of contaminants within the area.

Note: The different degrees of environmental control are defined inthe Supplementary Guidelines for the Manufacture of sterile medicinalproducts.

CLEAN/CONTAINED AREAAn area constructed and operated in such a manner that will achieve theaims of both a clean area and a contained area at the same time.

CONTAINMENTThe action of confining a biological agent or other entity within a definedspace.

Primary containment: A system of containment which prevents theescape of a biological agent into the immediate working environment. It


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involves the use of closed containers or safety biological cabinets alongwith secure operating procedures.

Secondary containment: A system of containment which prevents theescape of a biological agent into the external environment or into otherworking areas. It involves the use of rooms with specially designed airhandling, the existence of airlocks and/or sterilisers for the exit of mate-rials and secure operating procedures. In many cases it may add to theeffectiveness of primary containment.

CONTAINED AREAAn area constructed and operated in such a manner (and equipped withappropriate air handling and filtration) so as to prevent contamination ofthe external environment by biological agents from within the area.

CONTROLLED AREAAn area constructed and operated in such a manner that some attempt ismade to control the introduction of potential contamination (an air supplyapproximating to grade D may be appropriate), and the consequences ofaccidental release of living organisms. The level of control exercised shouldreflect the nature of the organism employed in the process. At a minimum,the area should be maintained at a pressure negative to the immediateexternal environment and allow for the efficient removal of small quantitiesof airborne contaminants.

COMPUTERISED SYSTEMA system including the input of data, electronic processing and the outputof information to be used either for reporting or automatic control.

CROSS-CONTAMINATIONContamination of a material or of a product with another material orproduct.

CRUDE PLANT (VEGETABLE DRUG)Fresh or dried medicinal plant or parts thereof.

CRYOGENIC VESSELA container designed to contain liquefied gas at extremely low temperature.

CYLINDERA container designed to contain gas at a high pressure.

EXOTIC ORGANISMA biological agent where either the corresponding disease does not existin a given country or geographical area, or where the disease is the subjectof prophylactic measures or an eradication programme undertaken in thegiven country or geographical area.


FINISHED PRODUCTA medicinal product which has undergone all stages of production, includ-ing packaging in its final container.

HERBAL MEDICINAL PRODUCTMedicinal product containing, as active ingredients, exclusively plant mate-rial and/or vegetable drug preparations.

INFECTEDContaminated with extraneous biological agents and therefore capable ofspreading infection.

IN-PROCESS CONTROLChecks performed during production in order to monitor and if necessaryto adjust the process to ensure that the product conforms its specification.The control of the environment or equipment may also be regarded as apart of in-process control.

INTERMEDIATE PRODUCTPartly processed material which must undergo further manufacturing stepsbefore it becomes a bulk product.

LIQUIFIABLE GASESThose which, at the normal filling temperature and pressure, remain as aliquid in the cylinder.

MANIFOLDEquipment or apparatus designed to enable one or more gas containers tobe filled simultaneously from the same source.

MANUFACTUREAll operations of purchase of materials and products, Production, QualityControl, release, storage, distribution of medicinal products and the relatedcontrols.

MANUFACTURERHolder of a Manufacturing Authorisation as described in Article 40 ofDirective 2001/83/EC.

MEDICINAL PLANTPlant the whole or part of which is used for medicinal purpose.

MEDICINAL PRODUCTAny substance or combination of substances presented for treating or pre-venting disease in human beings or animals. Any substance or combinationof substances which may be administered to human beings or animals with


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a view to making a medical diagnosis or to restoring, correcting or mod-ifying physiological functions in human beings or in animals is likewiseconsidered a medicinal product.

PACKAGINGAll operations, including filling and labelling, which a bulk product has toundergo in order to become a finished product.

Note: Note Sterile filling would not normally be regarded as part of pack-aging, the bulk product being the filled, but not finally packaged, primarycontainers.

PACKAGING MATERIALAny material employed in the packaging of a medicinal product, exclud-ing any outer packaging used for transportation or shipment. Packagingmaterials are referred to as primary or secondary according to whether ornot they are intended to be in direct contact with the product.

PROCEDURESDescription of the operations to be carried out, the precautions to be takenand measures to be applied directly or indirectly related to the manufactureof a medicinal product.

PRODUCTIONAll operations involved in the preparation of a medicinal product, fromreceipt of materials, through processing and packaging, to its completionas a finished product.

QUALIFICATIONAction of proving that any equipment works correctly and actually leads tothe expected results. The word validation is sometimes widened to incor-porate the concept of qualification.

QUALITY CONTROLSee Section II, Chapter 1.

QUARANTINEThe status of starting or packaging materials, intermediate, bulk or finishedproducts isolated physically or by other effective means whilst awaiting adecision on their release or refusal.

RADIOPHARMACEUTICAL“Radiopharmaceutical” shall mean any medicinal product which, whenready for use, contains one or more radionuclides (radioactive isotopes)included for a medicinal purpose (Article 1(6) of Directive 2001/83/EC).


RECONCILIATIONA comparison, making due allowance for normal variation, between theamount of product or materials theoretically and actually produced orused.

RECORDSee Section II, Chapter 4.

RECOVERYThe introduction of all or part of previous batches of the required qualityinto another batch at a defined stage of manufacture.

REPROCESSINGThe reworking of all or part of a batch of product of an unacceptable qual-ity from a defined stage of production so that its quality may be renderedacceptable by one or more additional operations.

RETURNSending back to the manufacturer or distributor of a medicinal productwhich may or may not present a quality defect.

SEED LOTSeed lot system: A seed lot system is a system according to which successivebatches of a product are derived from the same master seed lot at a givenpassage level. For routine production, a working seed lot is prepared fromthe master seed lot. The final product is derived from the working seed lotand has not undergone more passages from the master seed lot than thevaccine shown in clinical studies to be satisfactory with respect to safetyand efficacy. The origin and the passage history of the master seed lot andthe working seed lot are recorded.

Master seed lot: A culture of a micro-organism distributed from a singlebulk into containers in a single operation in such a manner as to ensureuniformity, to prevent contamination and to ensure stability. A master seedlot in liquid form is usually stored at or below −70◦C. A freeze-dried masterseed lot is stored at a temperature known to ensure stability.

Working seed lot: A culture of a micro-organism derived from the mas-ter seed lot and intended for use in production. Working seed lots aredistributed into containers and stored as described above for master seedlots.

SPECIFICATIONSee Section II, Chapter 4.

STARTING MATERIALAny substance used in the production of a medicinal product, but excludingpackaging materials.


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STERILITYSterility is the absence of living organisms. The conditions of the sterilitytest are given in the European Pharmacopoeia.

SYSTEMIs used in the sense of a regulated pattern of interacting activities andtechniques which are united to form an organised whole.

VALIDATIONAction of proving, in accordance with the principles of Good Manufactur-ing Practice, that any procedure, process, equipment, material, activity orsystem actually leads to the expected results (see also qualification).

PART II: Basic Requirements for Active SubstancesUsed as Starting Materials

Contents of Part II

1 Introduction 2161.1 Objective 2161.2 Scope 216

2 Quality Management 2192.1 Principles 2192.2 Responsibilities of the Quality

Unit(s) 2202.3 Responsibility for Production

Activities 2212.4 Internal Audits (Self

Inspection) 2212.5 Product Quality Review 222

3 Personnel 2223.1 Personnel Qualifications 2223.2 Personnel Hygiene 2223.3 Consultants 223

4 Buildings and Facilities 2234.1 Design and Construction 2234.2 Utilities 2244.3 Water 2254.4 Containment 2254.5 Lighting 2264.6 Sewage and Refuse 2264.7 Sanitation and

Maintenance 2265 Process Equipment 226

5.1 Design and Construction 2265.2 Equipment Maintenance and

Cleaning 2275.3 Calibration 2285.4 Computerized Systems 228

6 Documentation and Records 2296.1 Documentation System and

Specifications 2296.2 Equipment Cleaning and Use

Record 230

6.3 Records of Raw Materials,Intermediates, API Labelling andPackaging Materials 231

6.4 Master Production Instructions(Master Production and ControlRecords) 231

6.5 Batch Production Records(Batch Production and ControlRecords) 232

6.6 Laboratory ControlRecords 233

6.7 Batch Production RecordReview 234

7 Materials Management 2347.1 General Controls 2347.2 Receipt and Quarantine 2357.3 Sampling and Testing of

Incoming ProductionMaterials 235

7.4 Storage 2367.5 Re-evaluation 236

8 Production and In-processControls 2378.1 Production Operations 2378.2 Time Limits 2378.3 In-process Sampling and

Controls 2388.4 Blending Batches of

Intermediates or APIs 2398.5 Contamination Control 239

9 Packaging and IdentificationLabelling of APIs andIntermediates 2409.1 General 2409.2 Packaging Materials 240

Contents continue214

EU Guidance on Good Manufacturing Practice 215

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9.3 Label Issuance andControl 240

9.4 Packaging and LabellingOperations 241

10 Storage and Distribution 24210.1 Warehousing

Procedures 24210.2 Distribution Procedures 242

11 Laboratory Controls 24311.1 General Controls 24311.2 Testing of Intermediates and

APIs 24411.3 Validation of Analytical

Procedures 24511.4 Certificates of Analysis 24511.5 Stability Monitoring of

APIs 24511.6 Expiry and Retest Dating 24611.7 Reserve/Retention

Samples 24612 Validation 247

12.1 Validation Policy 24712.2 Validation

Documentation 24712.3 Qualification 24812.4 Approaches to Process

Validation 24812.5 Process Validation

Program 24912.6 Periodic Review of Validated

Systems 25012.7 Cleaning Validation 25012.8 Validation of Analytical

Methods 25113 Change Control 25214 Rejection and Re-Use of

Materials 25214.1 Rejection 25214.2 Reprocessing 25314.3 Reworking 25314.4 Recovery of Materials and

Solvents 25414.5 Returns 254

15 Complaints and Recalls 25416 Contract Manufacturers

(including Laboratories) 25517 Agents, Brokers, Traders,

Distributors, Repackers, andRelabellers 25617.1 Applicability 25617.2 Traceability of Distributed

APIs and Intermediates 25617.3 Quality Management 25617.4 Repackaging, Relabelling and

Holding of APIs andIntermediates 256

17.5 Stability 25717.6 Transfer of Information 25717.7 Handling of Complaints and

Recalls 25717.8 Handling of Returns 258

18 Specific Guidance for APIsManufactured by CellCulture/Fermentation 25818.1 General 25818.2 Cell Bank Maintenance and

Recordkeeping 26018.3 Cell Culture/

Fermentation 26018.4 Harvesting, Isolation, and

Purification 26118.5 Viral Removal/Inactivation

Steps 26119 APIs for Use in Clinical Trials 262

19.1 General 26219.2 Quality 26219.3 Equipment and Facilities 26319.4 Control of Raw Materials 26319.5 Production 26319.6 Validation 26319.7 Changes 26419.8 Laboratory Controls 26419.9 Documentation 264

20 Glossary 264


1 Introduction

This guideline was published in November 2000 as Annex 18 to the GMPGuide reflecting the EU’s agreement to ICH Q7A and has been used bymanufacturers and GMP inspectorates on a voluntary basis. Article 46 (f)of Directive 2001/83/EC and Article 50 (f) of Directive 2001/82/EC; asamended by Directives 2004/27/EC and 2004/28/EC, respectively, placenew obligations on manufacturing authorisation holders to use only activesubstances that have been manufactured in accordance with Good Man-ufacturing Practice for starting materials. The directives go on to say thatthe principles of Good Manufacturing Practice for active substances areto be adopted as detailed guidelines. Member States have agreed that thetext of former Annex 18 should form the basis of the detailed guidelinesto create Part II of the GMP Guide.

1.1 Objective

These guidelines are intended to provide guidance regarding Good Manu-facturing Practice (GMP) for the manufacture of active substances underan appropriate system for managing quality. It is also intended to helpensure that active substances meet the requirements for quality and puritythat they purport or are represented to possess.

In these guidelines “manufacturing” includes all operations of receipt ofmaterials, production, packaging, repackaging, labelling, relabelling, qual-ity control, release, storage and distribution of active substances and therelated controls. The term “should” indicates recommendations that areexpected to apply unless shown to be inapplicable, modified in any relevantannexes to the GMP Guide, or replaced by an alternative demonstrated toprovide at least an equivalent level of quality assurance.

The GMP Guide as a whole does not cover safety aspects for the person-nel engaged in manufacture, nor aspects of protection of the environment.These controls are inherent responsibilities of the manufacturer and aregoverned by other parts of the legislation.

These guidelines are not intended to define registration requirementsor modify pharmacopoeial requirements and do not affect the abilityof the responsible competent authority to establish specific registrationrequirements regarding active substances within the context of market-ing/manufacturing authorisations. All commitments in registration docu-ments must be met.

1.2 Scope

These guidelines apply to the manufacture of active substances for medi-cinal products for both human and veterinary use. They apply to the


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manufacture of sterile active substances only up to the point immediatelyprior to the active substance being rendered sterile. The sterilisation andaseptic processing of sterile active substances are not covered, but shouldbe performed in accordance with the principles and guidelines of GMPas laid down in Directive 2003/94/EC and interpreted in the GMP Guideincluding its Annex 1.

In the case of ectoparasiticides for veterinary use, other standards thanthese guidelines, that ensure that the material is of appropriate quality, maybe used.

These guidelines exclude whole blood and plasma, as Directive2002/98/EC and the technical requirements supporting that directive laydown the detailed requirements for the collection and testing of blood;however, it does include active substances that are produced using bloodor plasma as raw materials.

Finally, these guidelines do not apply to bulk-packaged medicinal prod-ucts. They apply to all other active starting materials subject to any dero-gations described in the annexes to the GMP Guide, in particular Annexes2–7 where supplementary guidance for certain types of active substancemay be found. The annexes will consequently undergo a review but inthe meantime and only until this review is complete, manufacturers maychoose to continue to use Part I of the basic requirements and the rele-vant annexes for products covered by those annexes, or may already applyPart II.

Section 19 contains guidance that only applies to the manufacture ofactive substances used in the production of investigational medicinal prod-ucts although it should be noted that its application in this case, althoughrecommended, is not required by Community legislation.

An “Active Substance Starting Material” is a raw material, intermediateor an active substance that is used in the production of an active substanceand that is incorporated as a significant structural fragment into the struc-ture of the active substance. An Active Substance Starting Material can bean article of commerce, a material purchased from one or more suppli-ers under contract or commercial agreement, or produced in-house. ActiveSubstance Starting Materials normally have defined chemical propertiesand structure.

The manufacturer should designate and document the rationale for thepoint at which production of the active substance begins. For syntheticprocesses, this is known as the point at which “Active Substance StartingMaterials” are entered into the process.

For other processes (e.g. fermentation, extraction, purification, etc.), thisrationale should be established on a case-by-case basis. Table 1 gives guid-ance on the point at which the Active Substance Starting Material is nor-mally introduced into the process.

From this point on, appropriate GMP as defined in these guide-lines should be applied to these intermediate and/or active substance


Table 1 Application of this Guide to API Manufacturing

Type of Application of this Guide to steps (shown in grey) used in this typeManufacturing of manufacturing

ChemicalManufacturing

Productionof the APIStartingMaterial

Introductionof the APIStartingMaterial intoprocess

Production ofIntermediate(s)

Isolation andpurification

Physicalprocessing,andpackaging

API derived fromanimal sources

Collection oforgan, fluid,or tissue

Cutting,mixing,and/or initialprocessing

Introduction ofthe API StartingMaterial intoprocess



API extractedfrom plantsources

Collection ofplant

Cutting andinitialextraction(s)

Introduction ofthe API StartingMaterial intoprocess



Herbal extractsused as API

Collection ofplants

Cutting andinitialextraction

Furtherextraction


API consisting ofcomminuted orpowdered herbs

Collection ofplantsand/orcultivationandharvesting

Cutting/comminuting


Biotechnology:fermentation/cell culture

Establishmentof mastercell bankand workingcell bank

Maintenanceof workingcell bank

Cell cultureand/orfermentation



“Classical”Fermentation toproduce an API

Establishmentof cell bank

Maintenanceof the cellbank

Introduction ofthe cells intofermentation



Increasing GMP requirements


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manufacturing steps. This would include the validation of critical processsteps determined to impact the quality of the active substance. However,it should be noted that the fact that a manufacturer chooses to validate aprocess step does not necessarily define that step as critical.

The guidance in this document would normally be applied to the stepsshown in grey in Table 1. It does not imply that all steps shown shouldbe completed. The stringency of GMP in active substance manufacturingshould increase as the process proceeds from early steps to final steps, purifi-cation, and packaging. Physical processing of active substances, such asgranulation, coating or physical manipulation of particle size (e.g. milling,micronising), should be conducted at least to the standards of these guide-lines. These guidelines do not apply to steps prior to the first introductionof the defined “Active Substance Starting Material.”

In the remainder of this guideline the term Active Pharmaceutical Ingre-dient (API) is used repeatedly and should be considered interchangeablewith the term “Active Substance”. The glossary in Section 20 of Part IIshould only be applied in the context of Part II. Some of the same termsare already defined in Part I of the GMP guide and these, therefore, shouldonly be applied in the context of Part I.

2 Quality Management

2.1 Principles

2.10 Quality should be the responsibility of all persons involved in manufactur-ing.

2.11 Each manufacturer should establish, document, and implement an effec-tive system for managing quality that involves the active participation ofmanagement and appropriate manufacturing personnel.

2.12 The system for managing quality should encompass the organisationalstructure, procedures, processes and resources, as well as activities neces-sary to ensure confidence that the API will meet its intended specificationsfor quality and purity. All quality related activities should be defined anddocumented.

2.13 There should be a quality unit(s) that is independent of production andthat fulfils both quality assurance (QA) and quality control (QC) respon-sibilities. This can be in the form of separate QA and QC units or a singleindividual or group, depending upon the size and structure of the organi-zation.

2.14 The persons authorised to release intermediates and APIs should bespecified.


2.15 All quality related activities should be recorded at the time they are per-formed.

2.16 Any deviation from established procedures should be documented andexplained. Critical deviations should be investigated, and the investigationand its conclusions should be documented.

2.17 No materials should be released or used before the satisfactory completionof evaluation by the quality unit(s) unless there are appropriate systems inplace to allow for such use (e.g. release under quarantine as described inSection 10.20 or the use of raw materials or intermediates pending com-pletion of evaluation).

2.18 Procedures should exist for notifying responsible management in a timelymanner of regulatory inspections, serious GMP deficiencies, productdefects and related actions (e.g. quality related complaints, recalls, reg-ulatory actions, etc.).

2.2 Responsibilities of the Quality Unit(s)

2.20 The quality unit(s) should be involved in all quality-related matters.

2.21 The quality unit(s) should review and approve all appropriate quality-related documents.

2.22 The main responsibilities of the independent quality unit(s) should not bedelegated. These responsibilities should be described in writing and shouldinclude but not necessarily be limited to:

(1) releasing or rejecting all APIs. Releasing or rejecting intermediates foruse outside the control of the manufacturing company;

(2) establishing a system to release or reject raw materials, intermediates,packaging and labelling materials;

(3) reviewing completed batch production and laboratory control recordsof critical process steps before release of the API for distribution;

(4) making sure that critical deviations are investigated and resolved;(5) approving all specifications and master production instructions;(6) approving all procedures impacting the quality of intermediates or

APIs;(7) making sure that internal audits (self-inspections) are performed;(8) approving intermediate and API contract manufacturers;(9) approving changes that potentially impact intermediate or API qual-

ity;(10) reviewing and approving validation protocols and reports;(11) making sure that quality related complaints are investigated and

resolved;


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(12) making sure that effective systems are used for maintaining and cali-brating critical equipment;

(13) making sure that materials are appropriately tested and the results arereported;

(14) making sure that there is stability data to support retest or expiry datesand storage conditions on APIs and/or intermediates where appropri-ate; and

(15) performing product quality reviews (as defined in Section 2.5).

2.3 Responsibility for Production Activities

The responsibility for production activities should be described in writing,and should include but not necessarily be limited to:

(1) preparing, reviewing, approving and distributing the instructions forthe production of intermediates or APIs according to written pro-cedures;

(2) producing APIs and, when appropriate, intermediates according topre-approved instructions;

(3) reviewing all production batch records and ensuring that these arecompleted and signed;

(4) making sure that all production deviations are reported and evaluatedand that critical deviations are investigated and the conclusions arerecorded;

(5) making sure that production facilities are clean and when appropriatedisinfected;

(6) making sure that the necessary calibrations are performed and recordskept;

(7) making sure that the premises and equipment are maintained andrecords kept;

(8) making sure that validation protocols and reports are reviewed andapproved;

(9) evaluating proposed changes in product, process or equipment; and(10) making sure that new and, when appropriate, modified facilities and

equipment are qualified.

2.4 Internal Audits (Self Inspection)

2.40 In order to verify compliance with the principles of GMP for APIs, regu-lar internal audits should be performed in accordance with an approvedschedule.

2.41 Audit findings and corrective actions should be documented and broughtto the attention of responsible management of the firm. Agreed correctiveactions should be completed in a timely and effective manner.


2.5 Product Quality Review

2.50 Regular quality reviews of APIs should be conducted with the objective ofverifying the consistency of the process. Such reviews should normally beconducted and documented annually and should include at least:

� a review of critical in-process control and critical API test results;� a review of all batches that failed to meet established specification(s);� a review of all critical deviations or non-conformances and related

investigations;� a review of any changes carried out to the processes or analytical

methods;� a review of results of the stability monitoring programme;� a review of all quality-related returns, complaints and recalls; and� a review of adequacy of corrective actions.

2.51 The results of this review should be evaluated and an assessment made ofwhether corrective action or any revalidation should be undertaken. Rea-sons for such corrective action should be documented. Agreed correctiveactions should be completed in a timely and effective manner.

3 Personnel

3.1 Personnel Qualifications

3.10 There should be an adequate number of personnel qualified by appropriateeducation, training and/or experience to perform and supervise the manu-facture of intermediates and APIs.

3.11 The responsibilities of all personnel engaged in the manufacture of inter-mediates and APIs should be specified in writing.

3.12 Training should be regularly conducted by qualified individuals and shouldcover, at a minimum, the particular operations that the employee performsand GMP as it relates to the employee’s functions. Records of trainingshould be maintained. Training should be periodically assessed.

3.2 Personnel Hygiene

3.20 Personnel should practice good sanitation and health habits.

3.21 Personnel should wear clean clothing suitable for the manufacturing activ-ity with which they are involved and this clothing should be changed whenappropriate. Additional protective apparel, such as head, face, hand, andarm coverings, should be worn when necessary, to protect intermediatesand APIs from contamination.


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3.22 Personnel should avoid direct contact with intermediates or APIs.

3.23 Smoking, eating, drinking, chewing and the storage of food should berestricted to certain designated areas separate from the manufacturingareas.

3.24 Personnel suffering from an infectious disease or having open lesions onthe exposed surface of the body should not engage in activities that couldresult in compromising the quality of APIs. Any person shown at any time(either by medical examination or supervisory observation) to have anapparent illness or open lesions should be excluded from activities wherethe health condition could adversely affect the quality of the APIs untilthe condition is corrected or qualified medical personnel determine thatthe person’s inclusion would not jeopardize the safety or quality of theAPIs.

3.3 Consultants

3.30 Consultants advising on the manufacture and control of intermediates orAPIs should have sufficient education, training, and experience, or anycombination thereof, to advise on the subject for which they are retained.

3.31 Records should be maintained stating the name, address, qualifications,and type of service provided by these consultants.

4 Buildings and Facilities

4.1 Design and Construction

4.10 Buildings and facilities used in the manufacture of intermediates and APIsshould be located, designed, and constructed to facilitate cleaning, main-tenance, and operations as appropriate to the type and stage of manufac-ture. Facilities should also be designed to minimize potential contamina-tion. Where microbiological specifications have been established for theintermediate or API, facilities should also be designed to limit exposure toobjectionable microbiological contaminants as appropriate.

4.11 Buildings and facilities should have adequate space for the orderly place-ment of equipment and materials to prevent mix-ups and contamination.

4.12 Where the equipment itself (e.g., closed or contained systems) providesadequate protection of the material, such equipment can be located out-doors.

4.13 The flow of materials and personnel through the building or facilitiesshould be designed to prevent mix-ups or contamination.


4.14 There should be defined areas or other control systems for the followingactivities:

� Receipt, identification, sampling, and quarantine of incoming materials,pending release or rejection;

� Quarantine before release or rejection of intermediates and APIs;� Sampling of intermediates and APIs;� Holding rejected materials before further disposition (e.g., return, repro-

cessing or destruction)� Storage of released materials;� Production operations;� Packaging and labelling operations; and� Laboratory operations.

4.15 Adequate, clean washing and toilet facilities should be provided for person-nel. These washing facilities should be equipped with hot and cold wateras appropriate, soap or detergent, air driers or single service towels. Thewashing and toilet facilities should be separate from, but easily accessibleto, manufacturing areas. Adequate facilities for showering and/or changingclothes should be provided, when appropriate.

4.16 Laboratory areas/operations should normally be separated from produc-tion areas. Some laboratory areas, in particular those used for in-processcontrols, can be located in production areas, provided the operations ofthe production process do not adversely affect the accuracy of the labora-tory measurements, and the laboratory and its operations do not adverselyaffect the production process or intermediate or API.

4.2 Utilities

4.20 All utilities that could impact on product quality (e.g. steam, gases, com-pressed air, and heating, ventilation and air conditioning) should be qual-ified and appropriately monitored and action should be taken when limitsare exceeded. Drawings for these utility systems should be available.

4.21 Adequate ventilation, air filtration and exhaust systems should be pro-vided, where appropriate. These systems should be designed and con-structed to minimise risks of contamination and cross-contamination andshould include equipment for control of air pressure, micro-organisms (ifappropriate), dust, humidity, and temperature, as appropriate to the stageof manufacture. Particular attention should be given to areas where APIsare exposed to the environment.

4.22 If air is re-circulated to production areas, appropriate measures should betaken to control risks of contamination and cross-contamination.


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4.23 Permanently installed pipework should be appropriately identified. Thiscan be accomplished by identifying individual lines, documentation, com-puter control systems, or alternative means. Pipework should be locatedto avoid risks of contamination of the intermediate or API.

4.24 Drains should be of adequate size and should be provided with an air breakor a suitable device to prevent back-siphonage, when appropriate.

4.3 Water

4.30 Water used in the manufacture of APIs should be demonstrated to be suit-able for its intended use.

4.31 Unless otherwise justified, process water should, at a minimum, meetWorld Health Organization (WHO) guidelines for drinking (potable) waterquality.

4.32 If drinking (potable) water is insufficient to assure API quality, and tighterchemical and/or microbiological water quality specifications are called for,appropriate specifications for physical/chemical attributes, total microbialcounts, objectionable organisms and/or endotoxins should be established.

4.33 Where water used in the process is treated by the manufacturer to achievea defined quality, the treatment process should be validated and monitoredwith appropriate action limits.

4.34 Where the manufacturer of a non-sterile API either intends or claims that itis suitable for use in further processing to produce a sterile drug (medicinal)product, water used in the final isolation and purification steps should bemonitored and controlled for total microbial counts, objectionable organ-isms, and endotoxins.

4.4 Containment

4.40 Dedicated production areas, which can include facilities, air handlingequipment and/or process equipment, should be employed in the produc-tion of highly sensitizing materials, such as penicillins or cephalosporins.

4.41 Dedicated production areas should also be considered when material of aninfectious nature or high pharmacological activity or toxicity is involved(e.g., certain steroids or cytotoxic anti-cancer agents) unless validatedinactivation and/or cleaning procedures are established and maintained.

4.42 Appropriate measures should be established and implemented to preventcross-contamination from personnel, materials, etc. moving from one ded-icated area to another.


4.43 Any production activities (including weighing, milling, or packaging) ofhighly toxic non-pharmaceutical materials such as herbicides and pesticidesshould not be conducted using the buildings and/or equipment being usedfor the production of APIs. Handling and storage of these highly toxicnon-pharmaceutical materials should be separate from APIs.

4.5 Lighting

4.50 Adequate lighting should be provided in all areas to facilitate cleaning,maintenance, and proper operations.

4.6 Sewage and Refuse

4.60 Sewage, refuse, and other waste (e.g., solids, liquids, or gaseous by-products from manufacturing) in and from buildings and the immediatesurrounding area should be disposed of in a safe, timely, and sanitary man-ner. Containers and/or pipes for waste material should be clearly identified.

4.7 Sanitation and Maintenance

4.70 Buildings used in the manufacture of intermediates and APIs should beproperly maintained and repaired and kept in a clean condition.

4.71 Written procedures should be established assigning responsibility for san-itation and describing the cleaning schedules, methods, equipment, andmaterials to be used in cleaning buildings and facilities.

4.72 When necessary, written procedures should also be established for the useof suitable rodenticides, insecticides, fungicides, fumigating agents, andcleaning and sanitizing agents to prevent the contamination of equipment,raw materials, packaging/labelling materials, intermediates, and APIs.

5 Process Equipment

5.1 Design and Construction

5.10 Equipment used in the manufacture of intermediates and APIs should be ofappropriate design and adequate size, and suitably located for its intendeduse, cleaning, sanitization (where appropriate), and maintenance.

5.11 Equipment should be constructed so that surfaces that contact raw ma-terials, intermediates, or APIs do not alter the quality of the intermediatesand APIs beyond the official or other established specifications.


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5.12 Production equipment should only be used within its qualified operatingrange.

5.13 Major equipment (e.g., reactors, storage containers) and permanentlyinstalled processing lines used during the production of an intermediateor API should be appropriately identified.

5.14 Any substances associated with the operation of equipment, such as lubri-cants, heating fluids or coolants, should not contact intermediates or APIsso as to alter their quality beyond the official or other established specifi-cations. Any deviations from this should be evaluated to ensure that thereare no detrimental effects upon the fitness for purpose of the material.Wherever possible, food grade lubricants and oils should be used.

5.15 Closed or contained equipment should be used whenever appropriate.Where open equipment is used, or equipment is opened, appropriate pre-cautions should be taken to minimize the risk of contamination.

5.16 A set of current drawings should be maintained for equipment and criticalinstallations (e.g., instrumentation and utility systems).

5.2 Equipment Maintenance and Cleaning

5.20 Schedules and procedures (including assignment of responsibility) shouldbe established for the preventative maintenance of equipment.

5.21 Written procedures should be established for cleaning of equipment and itssubsequent release for use in the manufacture of intermediates and APIs.Cleaning procedures should contain sufficient details to enable operatorsto clean each type of equipment in a reproducible and effective manner.These procedures should include:

� Assignment of responsibility for cleaning of equipment;� Cleaning schedules, including, where appropriate, sanitizing schedules;� A complete description of the methods and materials, including dilution

of cleaning agents used to clean equipment;� When appropriate, instructions for disassembling and reassembling each

article of equipment to ensure proper cleaning;� Instructions for the removal or obliteration of previous batch identifica-

tion;� Instructions for the protection of clean equipment from contamination

prior to use;� Inspection of equipment for cleanliness immediately before use, if prac-

tical; and� Establishing the maximum time that may elapse between the completion

of processing and equipment cleaning, when appropriate.


5.22 Equipment and utensils should be cleaned, stored, and, where appropriate,sanitized or sterilized to prevent contamination or carry-over of a materialthat would alter the quality of the intermediate or API beyond the officialor other established specifications.

5.23 Where equipment is assigned to continuous production or campaign pro-duction of successive batches of the same intermediate or API, equipmentshould be cleaned at appropriate intervals to prevent build-up and carry-over of contaminants (e.g. degradants or objectionable levels of micro-organisms).

5.24 Non-dedicated equipment should be cleaned between production of differ-ent materials to prevent cross-contamination.

5.25 Acceptance criteria for residues and the choice of cleaning procedures andcleaning agents should be defined and justified.

5.26 Equipment should be identified as to its contents and its cleanliness statusby appropriate means.

5.3 Calibration

5.30 Control, weighing, measuring, monitoring and test equipment that is crit-ical for assuring the quality of intermediates or APIs should be calibratedaccording to written procedures and an established schedule.

5.31 Equipment calibrations should be performed using standards traceable tocertified standards, if existing.

5.32 Records of these calibrations should be maintained.

5.33 The current calibration status of critical equipment should be known andverifiable.

5.34 Instruments that do not meet calibration criteria should not be used.

5.35 Deviations from approved standards of calibration on critical instrumentsshould be investigated to determine if these could have had an impact on thequality of the intermediate(s) or API(s) manufactured using this equipmentsince the last successful calibration.

5.4 Computerized Systems

5.40 GMP related computerized systems should be validated. The depth andscope of validation depends on the diversity, complexity and criticality ofthe computerized application.


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5.41 Appropriate installation qualification and operational qualification shoulddemonstrate the suitability of computer hardware and software to performassigned tasks.

5.42 Commercially available software that has been qualified does not requirethe same level of testing. If an existing system was not validated at time ofinstallation, a retrospective validation could be conducted if appropriatedocumentation is available.

5.43 Computerized systems should have sufficient controls to prevent un-authorized access or changes to data. There should be controls to preventomissions in data (e.g. system turned off and data not captured). Thereshould be a record of any data change made, the previous entry, who madethe change, and when the change was made.

5.44 Written procedures should be available for the operation and maintenanceof computerized systems.

5.45 Where critical data are being entered manually, there should be an addi-tional check on the accuracy of the entry. This can be done by a secondoperator or by the system itself.

5.46 Incidents related to computerized systems that could affect the quality ofintermediates or APIs or the reliability of records or test results should berecorded and investigated.

5.47 Changes to the computerized system should be made according to achange procedure and should be formally authorized, documented andtested. Records should be kept of all changes, including modifications andenhancements made to the hardware, software and any other critical com-ponent of the system. These records should demonstrate that the system ismaintained in a validated state.

5.48 If system breakdowns or failures would result in the permanent loss ofrecords, a back-up system should be provided. A means of ensuring dataprotection should be established for all computerized systems.

5.49 Data can be recorded by a second means in addition to the computersystem.

6 Documentation and Records

6.1 Documentation System and Specifications

6.10 All documents related to the manufacture of intermediates or APIs shouldbe prepared, reviewed, approved and distributed according to writtenprocedures. Such documents can be in paper or electronic form.


6.11 The issuance, revision, superseding and withdrawal of all documentsshould be controlled with maintenance of revision histories.

6.12 A procedure should be established for retaining all appropriate documents(e.g., development history reports, scale-up reports, technical transferreports, process validation reports, training records, production records,control records, and distribution records). The retention periods for thesedocuments should be specified.

6.13 All production, control, and distribution records should be retained for atleast 1 year after the expiry date of the batch. For APIs with retest dates,records should be retained for at least 3 years after the batch is completelydistributed.

6.14 When entries are made in records, these should be made indelibly inspaces provided for such entries, directly after performing the activities,and should identify the person making the entry. Corrections to entriesshould be dated and signed and leave the original entry still readable.

6.15 During the retention period, originals or copies of records should be readilyavailable at the establishment where the activities described in such recordsoccurred. Records that can be promptly retrieved from another locationby electronic or other means are acceptable.

6.16 Specifications, instructions, procedures, and records can be retained eitheras originals or as true copies such as photocopies, microfilm, microfiche,or other accurate reproductions of the original records. Where reductiontechniques such as microfilming or electronic records are used, suitableretrieval equipment and a means to produce a hard copy should be readilyavailable.

6.17 Specifications should be established and documented for raw materials,intermediates where necessary, APIs, and labelling and packaging materi-als. In addition, specifications may be appropriate for certain other mate-rials, such as process aids, gaskets, or other materials used during the pro-duction of intermediates or APIs that could critically impact on quality.Acceptance criteria should be established and documented for in-processcontrols.

6.18 If electronic signatures are used on documents, they should be authenti-cated and secure.

6.2 Equipment Cleaning and Use Record

6.20 Records of major equipment use, cleaning, sanitization and/or sterilizationand maintenance should show the date, time (if appropriate), product, andbatch number of each batch processed in the equipment, and the personwho performed the cleaning and maintenance.


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6.21 If equipment is dedicated to manufacturing one intermediate or API, thenindividual equipment records are not necessary if batches of the intermedi-ate or API follow in traceable sequence. In cases where dedicated equipmentis employed, the records of cleaning, maintenance, and use can be part ofthe batch record or maintained separately.

6.3 Records of Raw Materials, Intermediates, API Labelling andPackaging Materials

6.30 Records should be maintained including:

� The name of the manufacturer, identity and quantity of each shipmentof each batch of raw materials, intermediates or labelling and packagingmaterials for APIs; the name of the supplier; the supplier’s control num-ber(s), if known, or other identification number; the number allocatedon receipt; and the date of receipt;

� The results of any test or examination performed and the conclusionsderived from this;

� Records tracing the use of materials;� Documentation of the examination and review of API labelling and pack-

aging materials for conformity with established specifications; and� The final decision regarding rejected raw materials, intermediates or API

labelling and packaging materials.

6.31 Master (approved) labels should be maintained for comparison to issuedlabels.

6.4 Master Production Instructions (Master Production andControl Records)

6.40 To ensure uniformity from batch to batch, master production instructionsfor each intermediate and API should be prepared, dated, and signed byone person and independently checked, dated, and signed by a person inthe quality unit(s).

6.41 Master production instructions should include:

� The name of the intermediate or API being manufactured and an iden-tifying document reference code, if applicable;

� A complete list of raw materials and intermediates designated by namesor codes sufficiently specific to identify any special quality characte-ristics;

� An accurate statement of the quantity or ratio of each raw material orintermediate to be used, including the unit of measure. Where the quan-tity is not fixed, the calculation for each batch size or rate of production


should be included. Variations to quantities should be included wherethey are justified;

� The production location and major production equipment to be used;� Detailed production instructions, including the:

� sequences to be followed;� ranges of process parameters to be used;� sampling instructions and in-process controls with their acceptance

criteria, where appropriate;� time limits for completion of individual processing steps and/or the

total process, where appropriate; and� expected yield ranges at appropriate phases of processing or time;

� Where appropriate, special notations and precautions to be followed, orcross references to these; and

� The instructions for storage of the intermediate or API to assure itssuitability for use, including the labelling and packaging materials andspecial storage conditions with time limits, where appropriate.

6.5 Batch Production Records (Batch Production andControl Records)

6.50 Batch production records should be prepared for each intermediate andAPI and should include complete information relating to the productionand control of each batch. The batch production record should be checkedbefore issuance to assure that it is the correct version and a legible accu-rate reproduction of the appropriate master production instruction. If thebatch production record is produced from a separate part of the masterdocument, that document should include a reference to the current masterproduction instruction being used.

6.51 These records should be numbered with a unique batch or identificationnumber, dated and signed when issued. In continuous production, the prod-uct code together with the date and time can serve as the unique identifieruntil the final number is allocated.

6.52 Documentation of completion of each significant step in the batch produc-tion records (batch production and control records) should include:

� Dates and, when appropriate, times;� Identity of major equipment (e.g., reactors, driers, mills, etc.) used;� Specific identification of each batch, including weights, measures, and

batch numbers of raw materials, intermediates, or any reprocessed ma-terials used during manufacturing;

� Actual results recorded for critical process parameters;� Any sampling performed;


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� Signatures of the persons performing and directly supervising or check-ing each critical step in the operation;

� In-process and laboratory test results;� Actual yield at appropriate phases or times;� Description of packaging and label for intermediate or API;� Representative label of API or intermediate if made commercially avail-

able;� Any deviation noted, its evaluation, investigation conducted (if appro-

priate) or reference to that investigation if stored separately; and� Results of release testing.

6.53 Written procedures should be established and followed for investigatingcritical deviations or the failure of a batch of intermediate or API to meetspecifications. The investigation should extend to other batches that mayhave been associated with the specific failure or deviation.

6.6 Laboratory Control Records

6.60 Laboratory control records should include complete data derived from alltests conducted to ensure compliance with established specifications andstandards, including examinations and assays, as follows:

� A description of samples received for testing, including the materialname or source, batch number or other distinctive code, date samplewas taken, and, where appropriate, the quantity and date the samplewas received for testing;

� A statement of or reference to each test method used;� A statement of the weight or measure of sample used for each test as

described by the method; data on or cross-reference to the preparationand testing of reference standards, reagents and standard solutions;

� A complete record of all raw data generated during each test, in additionto graphs, charts, and spectra from laboratory instrumentation, properlyidentified to show the specific material and batch tested;

� A record of all calculations performed in connection with the test, includ-ing, for example, units of measure, conversion factors, and equivalencyfactors;

� A statement of the test results and how they compare with establishedacceptance criteria;

� The signature of the person who performed each test and the date(s) thetests were performed; and

� The date and signature of a second person showing that the originalrecords have been reviewed for accuracy, completeness, and compliancewith established standards.

6.61 Complete records should also be maintained for:


� Any modifications to an established analytical method,� Periodic calibration of laboratory instruments, apparatus, gauges, and

recording devices;� All stability testing performed on APIs; and� Out-of-specification (OOS) investigations.

6.7 Batch Production Record Review

6.70 Written procedures should be established and followed for the review andapproval of batch production and laboratory control records, includingpackaging and labelling, to determine compliance of the intermediate orAPI with established specifications before a batch is released or distributed.

6.71 Batch production and laboratory control records of critical process stepsshould be reviewed and approved by the quality unit(s) before an APIbatch is released or distributed. Production and laboratory control recordsof non-critical process steps can be reviewed by qualified production per-sonnel or other units following procedures approved by the quality unit(s).

6.72 All deviation, investigation, and OOS reports should be reviewed as partof the batch record review before the batch is released.

6.73 The quality unit(s) can delegate to the production unit the responsibilityand authority for release of intermediates, except for those shipped outsidethe control of the manufacturing company.

7 Materials Management

7.1 General Controls

7.10 There should be written procedures describing the receipt, identification,quarantine, storage, handling, sampling, testing, and approval or rejectionof materials.

7.11 Manufacturers of intermediates and/or APIs should have a system for eval-uating the suppliers of critical materials.

7.12 Materials should be purchased against an agreed specification, from a sup-plier or suppliers approved by the quality unit(s).

7.13 If the supplier of a critical material is not the manufacturer of that ma-terial, the name and address of that manufacturer should be known by theintermediate and/or API manufacturer.

7.14 Changing the source of supply of critical raw materials should be treatedaccording to Section 13, Change Control.


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7.2 Receipt and Quarantine

7.20 Upon receipt and before acceptance, each container or grouping of contain-ers of materials should be examined visually for correct labelling (includingcorrelation between the name used by the supplier and the in-house name,if these are different), container damage, broken seals and evidence of tam-pering or contamination. Materials should be held under quarantine untilthey have been sampled, examined or tested as appropriate, and releasedfor use.

7.21 Before incoming materials are mixed with existing stocks (e.g., solventsor stocks in silos), they should be identified as correct, tested, if appropri-ate, and released. Procedures should be available to prevent dischargingincoming materials wrongly into the existing stock.

7.22 If bulk deliveries are made in non-dedicated tankers, there should be assur-ance of no cross-contamination from the tanker. Means of providing thisassurance could include one or more of the following:

� certificate of cleaning� testing for trace impurities� audit of the supplier.

7.23 Large storage containers, and their attendant manifolds, filling and dis-charge lines should be appropriately identified.

7.24 Each container or grouping of containers (batches) of materials should beassigned and identified with a distinctive code, batch, or receipt number.This number should be used in recording the disposition of each batch. Asystem should be in place to identify the status of each batch.

7.3 Sampling and Testing of Incoming Production Materials

7.30 At least one test to verify the identity of each batch of material should beconducted, with the exception of the materials described below in Section7.32. A supplier’s Certificate of Analysis can be used in place of performingother tests, provided that the manufacturer has a system in place to evaluatesuppliers.

7.31 Supplier approval should include an evaluation that provides adequateevidence (e.g., past quality history) that the manufacturer can consistentlyprovide material meeting specifications. Full analyses should be conductedon at least three batches before reducing in-house testing. However, as aminimum, a full analysis should be performed at appropriate intervals andcompared with the Certificates of Analysis. Reliability of Certificates ofAnalysis should be checked at regular intervals.


7.32 Processing aids, hazardous or highly toxic raw materials, other specialmaterials, or materials transferred to another unit within the company’scontrol do not need to be tested if the manufacturer’s Certificate of Anal-ysis is obtained, showing that these raw materials conform to establishedspecifications. Visual examination of containers, labels, and recording ofbatch numbers should help in establishing the identity of these materi-als. The lack of on-site testing for these materials should be justified anddocumented.

7.33 Samples should be representative of the batch of material from which theyare taken. Sampling methods should specify the number of containers tobe sampled, which part of the container to sample, and the amount ofmaterial to be taken from each container. The number of containers tosample and the sample size should be based upon a sampling plan thattakes into consideration the criticality of the material, material variability,past quality history of the supplier, and the quantity needed for analysis.

7.34 Sampling should be conducted at defined locations and by proceduresdesigned to prevent contamination of the material sampled and contami-nation of other materials.

7.35 Containers from which samples are withdrawn should be opened care-fully and subsequently re-closed. They should be marked to indicate thata sample has been taken.

7.4 Storage

7.40 Materials should be handled and stored in a manner to prevent degrada-tion, contamination, and cross-contamination.

7.41 Materials stored in fibre drums, bags, or boxes should be stored off the floorand, when appropriate, suitably spaced to permit cleaning and inspection.

7.42 Materials should be stored under conditions and for a period that have noadverse affect on their quality, and should normally be controlled so thatthe oldest stock is used first.

7.43 Certain materials in suitable containers can be stored outdoors, providedidentifying labels remain legible and containers are appropriately cleanedbefore opening and use.

7.44 Rejected materials should be identified and controlled under a quarantinesystem designed to prevent their unauthorised use in manufacturing.

7.5 Re-evaluation

7.50 Materials should be re-evaluated as appropriate to determine their suitabil-ity for use (e.g. after prolonged storage or exposure to heat or humidity).


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8 Production and In-Process Controls

8.1 Production Operations

8.10 Raw materials for intermediate and API manufacturing should be weighedor measured under appropriate conditions that do not affect their suitabil-ity for use. Weighing and measuring devices should be of suitable accuracyfor the intended use.

8.11 If a material is subdivided for later use in production operations, the con-tainer receiving the material should be suitable and should be so identifiedthat the following information is available:

� Material name and/or item code;� Receiving or control number;� Weight or measure of material in the new container; and� Re-evaluation or retest date if appropriate.

8.12 Critical weighing, measuring, or subdividing operations should be wit-nessed or subjected to an equivalent control. Prior to use, production per-sonnel should verify that the materials are those specified in the batchrecord for the intended intermediate or API.

8.13 Other critical activities should be witnessed or subjected to an equivalentcontrol.

8.14 Actual yields should be compared with expected yields at designated stepsin the production process. Expected yields with appropriate ranges shouldbe established based on previous laboratory, pilot scale, or manufacturingdata. Deviations in yield associated with critical process steps should beinvestigated to determine their impact or potential impact on the resultingquality of affected batches.

8.15 Any deviation should be documented and explained. Any critical deviationshould be investigated.

8.16 The processing status of major units of equipment should be indicatedeither on the individual units of equipment or by appropriate documenta-tion, computer control systems, or alternative means.

8.17 Materials to be reprocessed or reworked should be appropriately controlledto prevent unauthorized use.

8.2 Time Limits

8.20 If time limits are specified in the master production instruction (see Section6.41), these time limits should be met to ensure the quality of interme-diates and APIs. Deviations should be documented and evaluated. Time


limits may be inappropriate when processing to a target value (e.g., pHadjustment, hydrogenation, drying to predetermined specification) becausecompletion of reactions or processing steps are determined by in-processsampling and testing.

8.21 Intermediates held for further processing should be stored under appropri-ate conditions to ensure their suitability for use.

8.3 In-process Sampling and Controls

8.30 Written procedures should be established to monitor the progress and con-trol the performance of processing steps that cause variability in the qual-ity characteristics of intermediates and APIs. In-process controls and theiracceptance criteria should be defined based on the information gained dur-ing the development stage or historical data.

8.31 The acceptance criteria and type and extent of testing can depend on thenature of the intermediate or API being manufactured, the reaction orprocess step being conducted, and the degree to which the process intro-duces variability in the product’s quality. Less stringent in-process controlsmay be appropriate in early processing steps, whereas tighter controls maybe appropriate for later processing steps (e.g., isolation and purificationsteps).

8.32 Critical in-process controls (and critical process monitoring), including thecontrol points and methods, should be stated in writing and approved bythe quality unit(s).

8.33 In-process controls can be performed by qualified production departmentpersonnel and the process adjusted without prior quality unit(s) approvalif the adjustments are made within pre-established limits approved by thequality unit(s). All tests and results should be fully documented as part ofthe batch record.

8.34 Written procedures should describe the sampling methods for in-processmaterials, intermediates, and APIs. Sampling plans and procedures shouldbe based on scientifically sound sampling practices.

8.35 In-process sampling should be conducted using procedures designed toprevent contamination of the sampled material and other intermediates orAPIs. Procedures should be established to ensure the integrity of samplesafter collection.

8.36 Out-of-specification (OOS) investigations are not normally needed for in-process tests that are performed for the purpose of monitoring and/oradjusting the process.


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8.4 Blending Batches of Intermediates or APIs

8.40 For the purpose of this document, blending is defined as the process of com-bining materials within the same specification to produce a homogeneousintermediate or API. In-process mixing of fractions from single batches(e.g., collecting several centrifuge loads from a single crystallization batch)or combining fractions from several batches for further processing is con-sidered to be part of the production process and is not considered to beblending.

8.41 Out-of-specification batches should not be blended with other batches forthe purpose of meeting specifications. Each batch incorporated into theblend should have been manufactured using an established process andshould have been individually tested and found to meet appropriate spec-ifications prior to blending.

8.42 Acceptable blending operations include but are not limited to:

� Blending of small batches to increase batch size� Blending of tailings (i.e., relatively small quantities of isolated material)

from batches of the same intermediate or API to form a single batch.

8.43 Blending processes should be adequately controlled and documented andthe blended batch should be tested for conformance to established specifi-cations where appropriate.

8.44 The batch record of the blending process should allow traceability back tothe individual batches that make up the blend.

8.45 Where physical attributes of the API are critical (e.g., APIs intended for usein solid oral dosage forms or suspensions), blending operations should bevalidated to show homogeneity of the combined batch. Validation shouldinclude testing of critical attributes (e.g., particle size distribution, bulkdensity, and tap density) that may be affected by the blending process.

8.46 If the blending could adversely affect stability, stability testing of the finalblended batches should be performed.

8.47 The expiry or retest date of the blended batch should be based on themanufacturing date of the oldest tailings or batch in the blend.

8.5 Contamination Control

8.50 Residual materials can be carried over into successive batches of the sameintermediate or API if there is adequate control. Examples include residueadhering to the wall of a micronizer, residual layer of damp crystals remain-ing in a centrifuge bowl after discharge, and incomplete discharge of fluidsor crystals from a processing vessel upon transfer of the material to the


next step in the process. Such carryover should not result in the carry-over of degradants or microbial contamination that may adversely alterthe established API impurity profile.

8.51 Production operations should be conducted in a manner that will preventcontamination of intermediates or APIs by other materials.

8.52 Precautions to avoid contamination should be taken when APIs are handledafter purification.

9 Packaging and Identification Labelling ofAPIs and Intermediates

9.1 General

9.10 There should be written procedures describing the receipt, identification,quarantine, sampling, examination and/or testing and release, and handlingof packaging and labelling materials.

9.11 Packaging and labelling materials should conform to established specifica-tions. Those that do not comply with such specifications should be rejectedto prevent their use in operations for which they are unsuitable.

9.12 Records should be maintained for each shipment of labels and packagingmaterials showing receipt, examination, or testing, and whether acceptedor rejected.

9.2 Packaging Materials

9.20 Containers should provide adequate protection against deterioration orcontamination of the intermediate or API that may occur during trans-portation and recommended storage.

9.21 Containers should be clean and, where indicated by the nature of the inter-mediate or API, sanitized to ensure that they are suitable for their intendeduse. These containers should not be reactive, additive, or absorptive so asto alter the quality of the intermediate or API beyond the specified limits.

9.22 If containers are re-used, they should be cleaned in accordance with docu-mented procedures and all previous labels should be removed or defaced.

9.3 Label Issuance and Control

9.30 Access to the label storage areas should be limited to authorised personnel.


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9.31 Procedures should be used to reconcile the quantities of labels issued, usedand returned and to evaluate discrepancies found between the number ofcontainers labelled and the number of labels issued. Such discrepanciesshould be investigated, and the investigation should be approved by thequality unit(s).

9.32 All excess labels bearing batch numbers or other batch-related printingshould be destroyed. Returned labels should be maintained and stored ina manner that prevents mix-ups and provides proper identification.

9.33 Obsolete and out-dated labels should be destroyed.

9.34 Printing devices used to print labels for packaging operations should becontrolled to ensure that all imprinting conforms to the print specified inthe batch production record.

9.35 Printed labels issued for a batch should be carefully examined for properidentity and conformity to specifications in the master production record.The results of this examination should be documented.

9.36 A printed label representative of those used should be included in the batchproduction record.

9.4 Packaging and Labelling Operations

9.40 There should be documented procedures designed to ensure that correctpackaging materials and labels are used.

9.41 Labelling operations should be designed to prevent mix-ups. There shouldbe physical or spatial separation from operations involving other inter-mediates or APIs.

9.42 Labels used on containers of intermediates or APIs should indicate thename or identifying code, the batch number of the product, and storageconditions, when such information is critical to assure the quality of inter-mediate or API.

9.43 If the intermediate or API is intended to be transferred outside the controlof the manufacturer’s material management system, the name and addressof the manufacturer, quantity of contents, and special transport conditionsand any special legal requirements should also be included on the label.For intermediates or APIs with an expiry date, the expiry date should beindicated on the label and Certificate of Analysis. For intermediates or APIswith a retest date, the retest date should be indicated on the label and/orCertificate of Analysis.

9.44 Packaging and labelling facilities should be inspected immediately beforeuse to ensure that all materials not needed for the next packaging operation


have been removed. This examination should be documented in the batchproduction records, the facility log, or other documentation system.

9.45 Packaged and labelled intermediates or APIs should be examined to ensurethat containers and packages in the batch have the correct label. This exam-ination should be part of the packaging operation. Results of these exam-inations should be recorded in the batch production or control records.

9.46 Intermediate or API containers that are transported outside of the manu-facturer’s control should be sealed in a manner such that, if the seal isbreached or missing, the recipient will be alerted to the possibility that thecontents may have been altered.

10 Storage and Distribution

10.1 Warehousing Procedures

10.10 Facilities should be available for the storage of all materials under appropri-ate conditions (e.g. controlled temperature and humidity when necessary).Records should be maintained of these conditions if they are critical forthe maintenance of material characteristics.

10.11 Unless there is an alternative system to prevent the unintentional or un-authorised use of quarantined, rejected, returned, or recalled materials,separate storage areas should be assigned for their temporary storage untilthe decision as to their future use has been taken.

10.2 Distribution Procedures

10.20 APIs and intermediates should only be released for distribution to thirdparties after they have been released by the quality unit(s). APIs and inter-mediates can be transferred under quarantine to another unit under thecompany’s control when authorized by the quality unit(s) and if appropri-ate controls and documentation are in place.

10.21 APIs and intermediates should be transported in a manner that does notadversely affect their quality.

10.22 Special transport or storage conditions for an API or intermediate shouldbe stated on the label.

10.23 The manufacturer should ensure that the contract acceptor (contractor) fortransportation of the API or intermediate knows and follows the appro-priate transport and storage conditions.

10.24 A system should be in place by which the distribution of each batch ofintermediate and/or API can be readily determined to permit its recall.


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11 Laboratory Controls

11.1 General Controls

11.10 The independent quality unit(s) should have at its disposal adequate labo-ratory facilities.

11.11 There should be documented procedures describing sampling, testing,approval or rejection of materials, and recording and storage of labora-tory data. Laboratory records should be maintained in accordance withSection 6.6.

11.12 All specifications, sampling plans, and test procedures should be scientif-ically sound and appropriate to ensure that raw materials, intermediates,APIs, and labels and packaging materials conform to established standardsof quality and/or purity. Specifications and test procedures should be con-sistent with those included in the registration/filing. There can be specifica-tions in addition to those in the registration/filing. Specifications, samplingplans, and test procedures, including changes to them, should be draftedby the appropriate organizational unit and reviewed and approved by thequality unit(s).

11.13 Appropriate specifications should be established for APIs in accor-dance with accepted standards and consistent with the manufac-turing process. The specifications should include a control of theimpurities (e.g. organic impurities, inorganic impurities, and residualsolvents). If the API has a specification for microbiological purity,appropriate action limits for total microbial counts and objectionableorganisms should be established and met. If the API has a specifica-tion for endotoxins, appropriate action limits should be established andmet.

11.14 Laboratory controls should be followed and documented at the time ofperformance. Any departures from the above described procedures shouldbe documented and explained.

11.15 Any out-of-specification result obtained should be investigated and docu-mented according to a procedure. This procedure should require analysisof the data, assessment of whether a significant problem exists, allocationof the tasks for corrective actions, and conclusions. Any re-sampling and/orretesting after OOS results should be performed according to a documentedprocedure.

11.16 Reagents and standard solutions should be prepared and labelled followingwritten procedures. “Use by” dates should be applied as appropriate foranalytical reagents or standard solutions.


11.17 Primary reference standards should be obtained as appropriate for themanufacture of APIs. The source of each primary reference standard shouldbe documented. Records should be maintained of each primary referencestandard’s storage and use in accordance with the supplier’s recommenda-tions. Primary reference standards obtained from an officially recognisedsource are normally used without testing if stored under conditions con-sistent with the supplier’s recommendations.

11.18 Where a primary reference standard is not available from an officiallyrecognized source, an “in-house primary standard” should be established.Appropriate testing should be performed to establish fully the identity andpurity of the primary reference standard. Appropriate documentation ofthis testing should be maintained.

11.19 Secondary reference standards should be appropriately prepared, identi-fied, tested, approved, and stored. The suitability of each batch of sec-ondary reference standard should be determined prior to first use by com-paring against a primary reference standard. Each batch of secondary ref-erence standard should be periodically requalified in accordance with awritten protocol.

11.2 Testing of Intermediates and APIs

11.20 For each batch of intermediate and API, appropriate laboratory tests shouldbe conducted to determine conformance to specifications.

11.21 An impurity profile describing the identified and unidentified impuritiespresent in a typical batch produced by a specific controlled productionprocess should normally be established for each API. The impurity profileshould include the identity or some qualitative analytical designation (e.g.retention time), the range of each impurity observed, and classification ofeach identified impurity (e.g. inorganic, organic, solvent). The impurityprofile is normally dependent upon the production process and origin ofthe API. Impurity profiles are normally not necessary for APIs from herbalor animal tissue origin. Biotechnology considerations are covered in ICHGuideline Q6B.

11.22 The impurity profile should be compared at appropriate intervals againstthe impurity profile in the regulatory submission or compared against his-torical data in order to detect changes to the API resulting from modifica-tions in raw materials, equipment operating parameters, or the productionprocess.

11.23 Appropriate microbiological tests should be conducted on each batch ofintermediate and API where microbial quality is specified.


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11.3 Validation of Analytical Procedures

See Section 12.

11.4 Certificates of Analysis

11.40 Authentic Certificates of Analysis should be issued for each batch of inter-mediate or API on request.

11.41 Information on the name of the intermediate or API including where appro-priate its grade, the batch number, and the date of release should be pro-vided on the Certificate of Analysis. For intermediates or APIs with anexpiry date, the expiry date should be provided on the label and Certificateof Analysis. For intermediates or APIs with a retest date, the retest dateshould be indicated on the label and/or Certificate of Analysis.

11.42 The Certificate should list each test performed in accordance with com-pendial or customer requirements, including the acceptance limits, and thenumerical results obtained (if test results are numerical).

11.43 Certificates should be dated and signed by authorised personnel of thequality unit(s) and should show the name, address and telephone numberof the original manufacturer. Where the analysis has been carried out by arepacker or reprocessor, the Certificate of Analysis should show the name,address and telephone number of the repacker/ reprocessor and a referenceto the name of the original manufacturer.

11.44 If new Certificates are issued by or on behalf of repackers/ reprocessors,agents or brokers, these Certificates should show the name, address andtelephone number of the laboratory that performed the analysis. Theyshould also contain a reference to the name and address of the originalmanufacturer and to the original batch Certificate, a copy of which shouldbe attached.

11.5 Stability Monitoring of APIs

11.50 A documented, on-going testing program should be designed to monitor thestability characteristics of APIs, and the results should be used to confirmappropriate storage conditions and retest or expiry dates.

11.51 The test procedures used in stability testing should be validated and bestability indicating.

11.52 Stability samples should be stored in containers that simulate the marketcontainer. For example, if the API is marketed in bags within fibre drums,stability samples can be packaged in bags of the same material and insmaller-scale drums of similar or identical material composition to themarket drums.


11.53 Normally the first three commercial production batches should be placedon the stability monitoring program to confirm the retest or expiry date.However, where data from previous studies show that the API is expectedto remain stable for at least two years, fewer than three batches can beused.

11.54 Thereafter, at least one batch per year of API manufactured (unless none isproduced that year) should be added to the stability monitoring programand tested at least annually to confirm the stability.

11.55 For APIs with short shelf-lives, testing should be done more frequently. Forexample, for those biotechnological/biologic and other APIs with shelf-lives of one year or less, stability samples should be obtained and shouldbe tested monthly for the first three months, and at three month intervalsafter that. When data exist that confirm that the stability of the API is notcompromised, elimination of specific test intervals (e.g. 9-month testing)can be considered.

11.56 Where appropriate, the stability storage conditions should be consistentwith the ICH guidelines on stability.

11.6 Expiry and Retest Dating

11.60 When an intermediate is intended to be transferred outside the control ofthe manufacturer’s material management system and an expiry or retestdate is assigned, supporting stability information should be available (e.g.published data, test results).

11.61 An API expiry or retest date should be based on an evaluation of dataderived from stability studies. Common practice is to use a retest date, notan expiration date.

11.62 Preliminary API expiry or retest dates can be based on pilot scale batchesif (1) the pilot batches employ a method of manufacture and procedurethat simulates the final process to be used on a commercial manufacturingscale; and (2) the quality of the API represents the material to be made ona commercial scale.

11.63 A representative sample should be taken for the purpose of performing aretest.

11.7 Reserve/Retention Samples

11.70 The packaging and holding of reserve samples is for the purpose of potentialfuture evaluation of the quality of batches of API and not for future stabilitytesting purposes.


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11.71 Appropriately identified reserve samples of each API batch should beretained for one year after the expiry date of the batch assigned by themanufacturer, or for three years after distribution of the batch, whicheveris the longer. For APIs with retest dates, similar reserve samples shouldbe retained for three years after the batch is completely distributed by themanufacturer.

11.72 The reserve sample should be stored in the same packaging system in whichthe API is stored or in one that is equivalent to or more protective thanthe marketed packaging system. Sufficient quantities should be retained toconduct at least two full compendial analyses or, when there is no phar-macopoeial monograph, two full specification analyses.

12 Validation

12.1 Validation Policy

12.10 The company’s overall policy, intentions, and approach to validation,including the validation of production processes, cleaning procedures, ana-lytical methods, in-process control test procedures, computerized systems,and persons responsible for design, review, approval and documentationof each validation phase, should be documented.

12.11 The critical parameters/attributes should normally be identified during thedevelopment stage or from historical data, and the ranges necessary for thereproducible operation should be defined. This should include:

� Defining the API in terms of its critical product attributes;� Identifying process parameters that could affect the critical quality

attributes of the API;� Determining the range for each critical process parameter expected to

be used during routine manufacturing and process control.

12.12 Validation should extend to those operations determined to be critical tothe quality and purity of the API.

12.2 Validation Documentation

12.20 A written validation protocol should be established that specifies how val-idation of a particular process will be conducted. The protocol should bereviewed and approved by the quality unit(s) and other designated units.

12.21 The validation protocol should specify critical process steps and acceptancecriteria as well as the type of validation to be conducted (e.g. retrospective,prospective, concurrent) and the number of process runs.


12.22 A validation report that cross-references the validation protocol should beprepared, summarising the results obtained, commenting on any deviationsobserved, and drawing the appropriate conclusions, including recommend-ing changes to correct deficiencies.

12.23 Any variations from the validation protocol should be documented withappropriate justification.

12.3 Qualification

12.30 Before starting process validation activities, appropriate qualification ofcritical equipment and ancillary systems should be completed. Qualifica-tion is usually carried out by conducting the following activities, individu-ally or combined:

� Design Qualification (DQ): documented verification that the proposeddesign of the facilities, equipment, or systems is suitable for the intendedpurpose;

� Installation Qualification (IQ): documented verification that the equip-ment or systems, as installed or modified, comply with the approveddesign, the manufacturer’s recommendations and/or user requirements;

� Operational Qualification (OQ): documented verification that the equip-ment or systems, as installed or modified, perform as intended through-out the anticipated operating ranges;

� Performance Qualification (PQ): documented verification that the equip-ment and ancillary systems, as connected together, can perform effec-tively and reproducibly based on the approved process method andspecifications.

12.4 Approaches to Process Validation

12.40 Process Validation (PV) is the documented evidence that the process, oper-ated within established parameters, can perform effectively and repro-ducibly to produce an intermediate or API meeting its predeterminedspecifications and quality attributes.

12.41 There are three approaches to validation. Prospective validation is the pre-ferred approach, but there are exceptions where the other approaches canbe used. These approaches and their applicability are listed below.

12.42 Prospective validation should normally be performed for all API processesas defined in Section 12.12. Prospective validation performed on an APIprocess should be completed before the commercial distribution of the finaldrug product manufactured from that API.


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12.43 Concurrent validation can be conducted when data from replicate produc-tion runs are unavailable because only a limited number of API batches havebeen produced, API batches are produced infrequently, or API batches areproduced by a validated process that has been modified. Prior to the com-pletion of concurrent validation, batches can be released and used in finaldrug product for commercial distribution based on thorough monitoringand testing of the API batches.

12.44 An exception can be made for retrospective validation for well establishedprocesses that have been used without significant changes to API qual-ity due to changes in raw materials, equipment, systems, facilities, or theproduction process. This validation approach may be used where:

(1) Critical quality attributes and critical process parameters have beenidentified;

(2) Appropriate in-process acceptance criteria and controls have beenestablished;

(3) There have not been significant process/product failures attributableto causes other than operator error or equipment failures unrelated toequipment suitability; and

(4) Impurity profiles have been established for the existing API.

12.45 Batches selected for retrospective validation should be representative ofall batches made during the review period, including any batches thatfailed to meet specifications, and should be sufficient in number to demon-strate process consistency. Retained samples can be tested to obtain data toretrospectively validate the process.

12.5 Process Validation Program

12.50 The number of process runs for validation should depend on the complex-ity of the process or the magnitude of the process change being considered.For prospective and concurrent validation, three consecutive successfulproduction batches should be used as a guide, but there may be situationswhere additional process runs are warranted to prove consistency of theprocess (e.g., complex API processes or API processes with prolonged com-pletion times). For retrospective validation, generally data from ten to thirtyconsecutive batches should be examined to assess process consistency, butfewer batches can be examined if justified.

12.51 Critical process parameters should be controlled and monitored duringprocess validation studies. Process parameters unrelated to quality, suchas variables controlled to minimize energy consumption or equipment use,need not be included in the process validation.


12.52 Process validation should confirm that the impurity profile for each API iswithin the limits specified. The impurity profile should be comparable toor better than historical data and, where applicable, the profile determinedduring process development or for batches used for pivotal clinical andtoxicological studies.

12.6 Periodic Review of Validated Systems

12.60 Systems and processes should be periodically evaluated to verify that theyare still operating in a valid manner. Where no significant changes have beenmade to the system or process, and a quality review confirms that the systemor process is consistently producing material meeting its specifications,there is normally no need for revalidation.

12.7 Cleaning Validation

12.70 Cleaning procedures should normally be validated. In general, cleaningvalidation should be directed to situations or process steps where contam-ination or carryover of materials poses the greatest risk to API quality. Forexample, in early production it may be unnecessary to validate equipmentcleaning procedures where residues are removed by subsequent purificationsteps.

12.71 Validation of cleaning procedures should reflect actual equipment usagepatterns. If various APIs or intermediates are manufactured in the sameequipment and the equipment is cleaned by the same process, a represen-tative intermediate or API can be selected for cleaning validation. Thisselection should be based on the solubility and difficulty of cleaning andthe calculation of residue limits based on potency, toxicity, and stability.

12.72 The cleaning validation protocol should describe the equipment to becleaned, procedures, materials, acceptable cleaning levels, parameters tobe monitored and controlled, and analytical methods. The protocol shouldalso indicate the type of samples to be obtained and how they are collectedand labelled.

12.73 Sampling should include swabbing, rinsing, or alternative methods (e.g.,direct extraction), as appropriate, to detect both insoluble and solubleresidues. The sampling methods used should be capable of quantitativelymeasuring levels of residues remaining on the equipment surfaces aftercleaning. Swab sampling may be impractical when product contact sur-faces are not easily accessible due to equipment design and/or process limi-tations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with smallports or handling toxic materials, and small intricate equipment such asmicronizers and microfluidizers).


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12.74 Validated analytical methods having sensitivity to detect residues orcontaminants should be used. The detection limit for each analyticalmethod should be sufficiently sensitive to detect the established accept-able level of the residue or contaminant. The method’s attainable recoverylevel should be established. Residue limits should be practical, achiev-able, verifiable and based on the most deleterious residue. Limits canbe established based on the minimum known pharmacological, toxi-cological, or physiological activity of the API or its most deleteriouscomponent.

12.75 Equipment cleaning/sanitization studies should address microbiologicaland endotoxin contamination for those processes where there is a needto reduce total microbiological count or endotoxins in the API, or otherprocesses where such contamination could be of concern (e.g., non-sterileAPIs used to manufacture sterile products).

12.76 Cleaning procedures should be monitored at appropriate intervals aftervalidation to ensure that these procedures are effective when usedduring routine production. Equipment cleanliness can be monitoredby analytical testing and visual examination, where feasible. Visualinspection can allow detection of gross contamination concentrated insmall areas that could otherwise go undetected by sampling and/oranalysis.

12.8 Validation of Analytical Methods

12.80 Analytical methods should be validated unless the method employed isincluded in the relevant pharmacopoeia or other recognised standard ref-erence. The suitability of all testing methods used should nonetheless beverified under actual conditions of use and documented.

12.81 Methods should be validated to include consideration of character-istics included within the ICH guidelines on validation of analyticalmethods. The degree of analytical validation performed should reflectthe purpose of the analysis and the stage of the API productionprocess.

12.82 Appropriate qualification of analytical equipment should be consideredbefore starting validation of analytical methods.

12.83 Complete records should be maintained of any modification of a val-idated analytical method. Such records should include the reason forthe modification and appropriate data to verify that the modificationproduces results that are as accurate and reliable as the establishedmethod.


13 Change Control

13.10 A formal change control system should be established to evaluate allchanges that may affect the production and control of the intermediateor API.

13.11 Written procedures should provide for the identification, documentation,appropriate review, and approval of changes in raw materials, specifica-tions, analytical methods, facilities, support systems, equipment (includingcomputer hardware), processing steps, labelling and packaging materials,and computer software.

13.12 Any proposals for GMP relevant changes should be drafted, reviewed,and approved by the appropriate organisational units, and reviewed andapproved by the quality unit(s).

13.13 The potential impact of the proposed change on the quality of the inter-mediate or API should be evaluated. A classification procedure may helpin determining the level of testing, validation, and documentation neededto justify changes to a validated process. Changes can be classified (e.g.as minor or major) depending on the nature and extent of the changes,and the effects these changes may impart on the process. Scientific judge-ment should determine what additional testing and validation studies areappropriate to justify a change in a validated process.

13.14 When implementing approved changes, measures should be taken to ensurethat all documents affected by the changes are revised.

13.15 After the change has been implemented, there should be an evaluation ofthe first batches produced or tested under the change.

13.16 The potential for critical changes to affect established retest or expiry datesshould be evaluated. If necessary, samples of the intermediate or API pro-duced by the modified process can be placed on an accelerated stabilityprogram and/or can be added to the stability monitoring program.

13.17 Current dosage form manufacturers should be notified of changes fromestablished production and process control procedures that can impact thequality of the API.

14 Rejection and Re-Use of Materials

14.1 Rejection

14.10 Intermediates and APIs failing to meet established specifications shouldbe identified as such and quarantined. These intermediates or APIs can


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be reprocessed or reworked as described below. The final disposition ofrejected materials should be recorded.

14.2 Reprocessing

14.20 Introducing an intermediate or API, including one that does not conformto standards or specifications, back into the process and reprocessing byrepeating a crystallization step or other appropriate chemical or physicalmanipulation steps (e.g., distillation, filtration, chromatography, milling)that are part of the established manufacturing process is generally con-sidered acceptable. However, if such reprocessing is used for a majorityof batches, such reprocessing should be included as part of the standardmanufacturing process.

14.21 Continuation of a process step after an in-process control test has shownthat the step is incomplete is considered to be part of the normal process.This is not considered to be reprocessing.

14.22 Introducing unreacted material back into a process and repeating a chem-ical reaction is considered to be reprocessing unless it is part of the estab-lished process. Such reprocessing should be preceded by careful evalu-ation to ensure that the quality of the intermediate or API is not adverselyimpacted due to the potential formation of by-products and over-reactedmaterials.

14.3 Reworking

14.30 Before a decision is taken to rework batches that do not conform to estab-lished standards or specifications, an investigation into the reason for non-conformance should be performed.

14.31 Batches that have been reworked should be subjected to appropriateevaluation, testing, stability testing if warranted, and documentation toshow that the reworked product is of equivalent quality to that pro-duced by the original process. Concurrent validation is often the appro-priate validation approach for rework procedures. This allows a pro-tocol to define the rework procedure, how it will be carried out, andthe expected results. If there is only one batch to be reworked, thena report can be written and the batch released once it is found to beacceptable.

14.32 Procedures should provide for comparing the impurity profile of eachreworked batch against batches manufactured by the established pro-cess. Where routine analytical methods are inadequate to characterize thereworked batch, additional methods should be used.


14.4 Recovery of Materials and Solvents

14.40 Recovery (e.g. from mother liquor or filtrates) of reactants, intermediates,or the API is considered acceptable, provided that approved proceduresexist for the recovery and the recovered materials meet specifications suit-able for their intended use.

14.41 Solvents can be recovered and reused in the same processes or in differentprocesses, provided that the recovery procedures are controlled and mon-itored to ensure that solvents meet appropriate standards before reuse orco-mingling with other approved materials.

14.42 Fresh and recovered solvents and reagents can be combined if adequatetesting has shown their suitability for all manufacturing processes in whichthey may be used.

14.43 The use of recovered solvents, mother liquors, and other recoveredmaterials should be adequately documented.

14.5 Returns

14.50 Returned intermediates or APIs should be identified as such and quaran-tined.

14.51 If the conditions under which returned intermediates or APIs have beenstored or shipped before or during their return or the condition of theircontainers casts doubt on their quality, the returned intermediates or APIsshould be reprocessed, reworked, or destroyed, as appropriate.

14.52 Records of returned intermediates or APIs should be maintained. For eachreturn, documentation should include:

� Name and address of the consignee� Intermediate or API, batch number, and quantity returned� Reason for return� Use or disposal of the returned intermediate or API.

15 Complaints and Recalls

15.10 All quality related complaints, whether received orally or in writing, shouldbe recorded and investigated according to a written procedure.

15.11 Complaint records should include:

� Name and address of complainant;� Name (and, where appropriate, title) and phone number of person sub-

mitting the complaint;


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� Complaint nature (including name and batch number of the API);� Date complaint is received;� Action initially taken (including dates and identity of person taking the

action);� Any follow-up action taken;� Response provided to the originator of complaint (including date

response sent); and� Final decision on intermediate or API batch or lot.

15.12 Records of complaints should be retained in order to evaluate trends, prod-uct related frequencies, and severity with a view to taking additional, andif appropriate, immediate corrective action.

15.13 There should be a written procedure that defines the circumstances underwhich a recall of an intermediate or API should be considered.

15.14 The recall procedure should designate who should be involved in evaluatingthe information, how a recall should be initiated, who should be informedabout the recall, and how the recalled material should be treated.

15.15 In the event of a serious or potentially life-threatening situation, local,national, and/or international authorities should be informed and theiradvice sought.

16 Contract Manufacturers (including Laboratories)

16.10 All contract manufacturers (including laboratories) should comply withthe GMP defined in this Guide. Special consideration should be given tothe prevention of cross-contamination and to maintaining traceability.

16.11 Contract manufacturers (including laboratories) should be evaluated bythe contract giver to ensure GMP compliance of the specific operationsoccurring at the contract sites.

16.12 There should be a written and approved contract or formal agreementbetween the contract giver and the contract acceptor that defines in detailthe GMP responsibilities, including the quality measures, of each party.

16.13 The contract should permit the contract giver to audit the contract accep-tor’s facilities for compliance with GMP.

16.14 Where subcontracting is allowed, the contract acceptor should not pass toa third party any of the work entrusted to him under the contract withoutthe contract giver’s prior evaluation and approval of the arrangements.

16.15 Manufacturing and laboratory records should be kept at the site where theactivity occurs and be readily available.


16.16 Changes in the process, equipment, test methods, specifications, or othercontractual requirements should not be made unless the contract giver isinformed and approves the changes.

17 Agents, Brokers, Traders, Distributors,Repackers, and Relabellers

17.1 Applicability

17.10 This section applies to any party other than the original manufacturer whomay trade and/or take possession, repack, relabel, manipulate, distributeor store an API or intermediate.

17.11 All agents, brokers, traders, distributors, repackers, and relabellers shouldcomply with GMP as defined in this Guide.

17.2 Traceability of Distributed APIs and Intermediates

17.20 Agents, brokers, traders, distributors, repackers, or relabellers shouldmaintain complete traceability of APIs and intermediates that they dis-tribute. Documents that should be retained and available include:

� Identity of original manufacturer;� Address of original manufacturer;� Purchase orders;� Bills of lading (transportation documentation);� Receipt documents;� Name or designation of API or intermediate;� Manufacturer’s batch number;� Transportation and distribution records;� All authentic Certificates of Analysis, including those of the original

manufacturer;� Retest or expiry date.

17.3 Quality Management

17.30 Agents, brokers, traders, distributors, repackers, or relabellers shouldestablish, document and implement an effective system of managing qual-ity, as specified in Section 2.

17.4 Repackaging, Relabelling and Holding ofAPIs and Intermediates

17.40 Repackaging, relabelling and holding of APIs and intermediates shouldbe performed under appropriate GMP controls, as stipulated in this


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Guide, to avoid mix-ups and loss of API or intermediate identity orpurity.

17.41 Repackaging should be conducted under appropriate environmental con-ditions to avoid contamination and cross-contamination.

17.5 Stability

17.50 Stability studies to justify assigned expiration or retest dates should beconducted if the API or intermediate is repackaged in a different type ofcontainer than that used by the API or intermediate manufacturer.

17.6 Transfer of Information

17.60 Agents, brokers, distributors, repackers, or relabellers should transfer allquality or regulatory information received from an API or intermediatemanufacturer to the customer, and from the customer to the API or inter-mediate manufacturer.

17.61 The agent, broker, trader, distributor, repacker, or relabeller who sup-plies the API or intermediate to the customer should provide the nameof the original API or intermediate manufacturer and the batch number(s)supplied.

17.62 The agent should also provide the identity of the original API or intermedi-ate manufacturer to regulatory authorities upon request. The original man-ufacturer can respond to the regulatory authority directly or through itsauthorized agents, depending on the legal relationship between the autho-rized agents and the original API or intermediate manufacturer. (In thiscontext “authorized” refers to authorized by the manufacturer.)

17.63 The specific guidance for Certificates of Analysis included in Section 11.4should be met.

17.7 Handling of Complaints and Recalls

17.70 Agents, brokers, traders, distributors, repackers or relabellers should main-tain records of complaints and recalls, as specified in Section 15, for allcomplaints and recalls that come to their attention.

17.71 If the situation warrants, the agents, brokers, traders, distributors, repack-ers, or relabellers should review the complaint with the original API or inter-mediate manufacturer in order to determine whether any further action,either with other customers who may have received this API or intermediateor with the regulatory authority, or both, should be initiated. The investi-gation into the cause for the complaint or recall should be conducted anddocumented by the appropriate party.


17.72 Where a complaint is referred to the original API or intermediate manufac-turer, the record maintained by the agents, brokers, traders, distributors,repackers, or relabellers should include any response received from theoriginal API or intermediate manufacturer (including date and informa-tion provided).

17.8 Handling of Returns

17.80 Returns should be handled as specified in Section 14.52. The agents,brokers, traders, distributors, repackers, or relabellers should maintaindocumentation of returned APIs and intermediates.

18 Specific Guidance for APIs Manufactured by CellCulture/Fermentation

18.1 General

18.10 Section 18 is intended to address specific controls for APIs or intermediatesmanufactured by cell culture or fermentation using natural or recombi-nant organisms and that have not been covered adequately in the previoussections. It is not intended to be a stand-alone section. In general, theGMP principles in the other sections of this document apply. Note thatthe principles of fermentation for “classical” processes for production ofsmall molecules and for processes using recombinant and non-recombinantorganisms for production of proteins and/or polypeptides are the same,although the degree of control will differ. Where practical, this section willaddress these differences. In general, the degree of control for biotechno-logical processes used to produce proteins and polypeptides is greater thanthat for classical fermentation processes.

18.11 The term “biotechnological process” (biotech) refers to the use of cells ororganisms that have been generated or modified by recombinant DNA,hybridoma or other technology to produce APIs. The APIs produced bybiotechnological processes normally consist of high molecular weight sub-stances, such as proteins and polypeptides, for which specific guidance isgiven in this section. Certain APIs of low molecular weight, such as anti-biotics, amino acids, vitamins, and carbohydrates, can also be producedby recombinant DNA technology. The level of control for these types ofAPI is similar to that employed for classical fermentation.

18.12 The term “classical fermentation” refers to processes that use micro-organisms existing in nature and/or modified by conventional methods(e.g. irradiation or chemical mutagenesis) to produce APIs. APIs producedby “classical fermentation” are normally low molecular weight productssuch as antibiotics, amino acids, vitamins, and carbohydrates.


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18.13 Production of APIs or intermediates from cell culture or fermentationinvolves biological processes such as cultivation of cells or extraction andpurification of material from living organisms. Note that there may be addi-tional process steps, such as physicochemical modification, that are part ofthe manufacturing process. The raw materials used (media, buffer compo-nents) may provide the potential for growth of microbiological contami-nants. Depending on the source, method of preparation, and the intendeduse of the API or intermediate, control of bioburden, viral contamination,and/or endotoxins during manufacturing and monitoring of the process atappropriate stages may be necessary.

18.14 Appropriate controls should be established at all stages of manufactur-ing to assure intermediate and/or API quality. While this Guide starts atthe cell culture/fermentation step, prior steps (e.g. cell banking) should beperformed under appropriate process controls. This Guide covers cell cul-ture/fermentation from the point at which a vial of the cell bank is retrievedfor use in manufacturing.

18.15 Appropriate equipment and environmental controls should be used to min-imize the risk of contamination. The acceptance criteria for quality of theenvironment and the frequency of monitoring should depend on the stepin production and the production conditions (open, closed, or containedsystems).

18.16 In general, process controls should take into account:

� Maintenance of the working cell bank (where appropriate);� Proper inoculation and expansion of the culture;� Control of the critical operating parameters during fermentation/cell

culture;� Monitoring of the process for cell growth, viability (for most cell culture

processes) and productivity where appropriate;� Harvest and purification procedures that remove cells, cellular debris

and media components while protecting the intermediate or API fromcontamination (particularly of a microbiological nature) and from lossof quality;

� Monitoring of bioburden and, where needed, endotoxin levels at appro-priate stages of production; and

� Viral safety concerns as described in ICH Guideline Q5A Quality ofBiotechnological Products: Viral Safety Evaluation of BiotechnologyProducts Derived from Cell Lines of Human or Animal Origin.

18.17 Where appropriate, the removal of media components, host cell proteins,other process-related impurities, product-related impurities and contami-nants should be demonstrated.


18.2 Cell Bank Maintenance and Record Keeping

18.20 Access to cell banks should be limited to authorized personnel.

18.21 Cell banks should be maintained under storage conditions designed tomaintain viability and prevent contamination.

18.22 Records of the use of the vials from the cell banks and storage conditionsshould be maintained.

18.23 Where appropriate, cell banks should be periodically monitored to deter-mine suitability for use.

18.24 See ICH Guideline Q5D Quality of Biotechnological Products: Derivationand Characterization of Cell Substrates Used for Production of Biotechno-logical/Biological Products for a more complete discussion of cell banking.

18.3 Cell Culture/Fermentation

18.30 Where aseptic addition of cell substrates, media, buffers, and gases isneeded, closed or contained systems should be used where possible. Ifthe inoculation of the initial vessel or subsequent transfers or additions(media, buffers) are performed in open vessels, there should be controlsand procedures in place to minimize the risk of contamination.

18.31 Where the quality of the API can be affected by microbial contamination,manipulations using open vessels should be performed in a biosafety cab-inet or similarly controlled environment.

18.32 Personnel should be appropriately gowned and take special precautionshandling the cultures.

18.33 Critical operating parameters (for example temperature, pH, agitationrates, addition of gases, pressure) should be monitored to ensure consis-tency with the established process. Cell growth, viability (for most cellculture processes), and, where appropriate, productivity should also bemonitored. Critical parameters will vary from one process to another, andfor classical fermentation, certain parameters (cell viability, for example)may not need to be monitored.

18.34 Cell culture equipment should be cleaned and sterilized after use. As appro-priate, fermentation equipment should be cleaned, and sanitized or steril-ized.

18.35 Culture media should be sterilized before use when appropriate to protectthe quality of the API.

18.36 There should be appropriate procedures in place to detect contamina-tion and determine the course of action to be taken. This should include


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procedures to determine the impact of the contamination on the productand those to decontaminate the equipment and return it to a condition tobe used in subsequent batches. Foreign organisms observed during fermen-tation processes should be identified as appropriate and the effect of theirpresence on product quality should be assessed, if necessary. The results ofsuch assessments should be taken into consideration in the disposition ofthe material produced.

18.37 Records of contamination events should be maintained.

18.38 Shared (multi-product) equipment may warrant additional testing aftercleaning between product campaigns, as appropriate, to minimize the riskof cross-contamination.

18.4 Harvesting, Isolation and Purification

18.40 Harvesting steps, either to remove cells or cellular components or to collectcellular components after disruption, should be performed in equipmentand areas designed to minimize the risk of contamination.

18.41 Harvest and purification procedures that remove or inactivate the pro-ducing organism, cellular debris and media components (while mini-mizing degradation, contamination, and loss of quality) should be ade-quate to ensure that the intermediate or API is recovered with consistentquality.

18.42 All equipment should be properly cleaned and, as appropriate, sanitizedafter use. Multiple successive batching without cleaning can be used ifintermediate or API quality is not compromised.

18.43 If open systems are used, purification should be performed under environ-mental conditions appropriate for the preservation of product quality.

18.44 Additional controls, such as the use of dedicated chromatography resinsor additional testing, may be appropriate if equipment is to be used formultiple products.

18.5 Viral Removal/Inactivation Steps

18.50 See the ICH Guideline Q5A Quality of Biotechnological Products: ViralSafety Evaluation of Biotechnology Products Derived from Cell Lines ofHuman or Animal Origin for more specific information.

18.51 Viral removal and viral inactivation steps are critical processing steps forsome processes and should be performed within their validated parameters.

18.52 Appropriate precautions should be taken to prevent potential viral contam-ination from pre-viral to post-viral removal/inactivation steps. Therefore,


open processing should be performed in areas that are separate from otherprocessing activities and have separate air handling units.

18.53 The same equipment is not normally used for different purification steps.However, if the same equipment is to be used, the equipment should beappropriately cleaned and sanitized before reuse. Appropriate precautionsshould be taken to prevent potential virus carry-over (e.g. through equip-ment or environment) from previous steps.

19 APIs for Use in Clinical Trials

19.1 General

19.10 Not all the controls in the previous sections of this Guide are appropriatefor the manufacture of a new API for investigational use during its develop-ment. Section 19 provides specific guidance unique to these circumstances.

19.11 The controls used in the manufacture of APIs for use in clinical trials shouldbe consistent with the stage of development of the drug product incorpo-rating the API. Process and test procedures should be flexible to provide forchanges as knowledge of the process increases and clinical testing of a drugproduct progresses from pre-clinical stages through clinical stages. Oncedrug development reaches the stage where the API is produced for use indrug products intended for clinical trials, manufacturers should ensure thatAPIs are manufactured in suitable facilities using appropriate productionand control procedures to ensure the quality of the API.

19.2 Quality

19.20 Appropriate GMP concepts should be applied in the production of APIsfor use in clinical trials with a suitable mechanism of approval of eachbatch.

19.21 A quality unit(s) independent from production should be established forthe approval or rejection of each batch of API for use in clinical trials.

19.22 Some of the testing functions commonly performed by the quality unit(s)can be performed within other organizational units.

19.23 Quality measures should include a system for testing of raw materials,packaging materials, intermediates, and APIs.

19.24 Process and quality problems should be evaluated.

19.25 Labelling for APIs intended for use in clinical trials should be appropriatelycontrolled and should identify the material as being for investigational use.


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19.3 Equipment and Facilities

19.30 During all phases of clinical development, including the use of small-scalefacilities or laboratories to manufacture batches of APIs for use in clinicaltrials, procedures should be in place to ensure that equipment is calibrated,clean and suitable for its intended use.

19.31 Procedures for the use of facilities should ensure that materials arehandled in a manner that minimizes the risk of contamination and cross-contamination.

19.4 Control of Raw Materials

19.40 Raw materials used in production of APIs for use in clinical trials shouldbe evaluated by testing, or received with a supplier’s analysis and subjectedto identity testing. When a material is considered hazardous, a supplier’sanalysis should suffice.

19.41 In some instances, the suitability of a raw material can be determined beforeuse based on acceptability in small-scale reactions (i.e., use testing) ratherthan on analytical testing alone.

19.5 Production

19.50 The production of APIs for use in clinical trials should be documented inlaboratory notebooks, batch records, or by other appropriate means. Thesedocuments should include information on the use of production materials,equipment, processing, and scientific observations.

19.51 Expected yields can be more variable and less defined than the expectedyields used in commercial processes. Investigations into yield variations arenot expected.

19.6 Validation

19.60 Process validation for the production of APIs for use in clinical trials isnormally inappropriate, where a single API batch is produced or whereprocess changes during API development make batch replication difficult orinexact. The combination of controls, calibration, and, where appropriate,equipment qualification assures API quality during this development phase.

19.61 Process validation should be conducted in accordance with Section 12 whenbatches are produced for commercial use, even when such batches areproduced on a pilot or small scale.


19.7 Changes

19.70 Changes are expected during development, as knowledge is gained and theproduction is scaled up. Every change in the production, specifications, ortest procedures should be adequately recorded.

19.8 Laboratory Controls

19.80 While analytical methods performed to evaluate a batch of API for clinicaltrials may not yet be validated, they should be scientifically sound.

19.81 A system for retaining reserve samples of all batches should be in place.This system should ensure that a sufficient quantity of each reserve sampleis retained for an appropriate length of time after approval, termination,or discontinuation of an application.

19.82 Expiry and retest dating as defined in Section 11.6 applies to existing APIsused in clinical trials. For new APIs, Section 11.6 does not normally applyin early stages of clinical trials.

19.9 Documentation

19.90 A system should be in place to ensure that information gained duringthe development and the manufacture of APIs for use in clinical trials isdocumented and available.

19.91 The development and implementation of the analytical methods used tosupport the release of a batch of API for use in clinical trials should beappropriately documented.

19.92 A system for retaining production and control records and documentsshould be used. This system should ensure that records and documentsare retained for an appropriate length of time after the approval, termina-tion, or discontinuation of an application.

20 Glossary to Part II

Acceptance CriteriaNumerical limits, ranges, or other suitable measures for acceptance of testresults.

Active Pharmaceutical Ingredient (API) (or drug substance)Any substance or mixture of substances intended to be used in the manufac-ture of a drug (medicinal) product and that, when used in the production of


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a drug, becomes an active ingredient of the drug product. Such substancesare intended to furnish pharmacological activity or other direct effect inthe diagnosis, cure, mitigation, treatment, or prevention of disease or toaffect the structure and function of the body.

API Starting MaterialA raw material, intermediate, or an API that is used in the productionof an API and that is incorporated as a significant structural fragmentinto the structure of the API. An API starting material can be an article ofcommerce, a material purchased from one or more suppliers under contractor commercial agreement, or produced in-house. API starting materials arenormally of defined chemical properties and structure.

Batch (or Lot)A specific quantity of material produced in a process or series of processesso that it is expected to be homogeneous within specified limits. In the caseof continuous production, a batch may correspond to a defined fraction ofthe production. The batch size can be defined either by a fixed quantity orby the amount produced in a fixed time interval.

Batch Number (or Lot Number)A unique combination of numbers, letters, and/or symbols that identifies abatch (or lot) and from which the production and distribution history canbe determined.

BioburdenThe level and type (e.g. objectionable or not) of micro-organisms that canbe present in raw materials, API starting materials, intermediates or APIs.Bioburden should not be considered contamination unless the levels havebeen exceeded or defined objectionable organisms have been detected.

CalibrationThe demonstration that a particular instrument or device produces resultswithin specified limits by comparison with those produced by a referenceor traceable standard over an appropriate range of measurements.

Computer SystemA group of hardware components and associated software, designed andassembled to perform a specific function or group of functions.

Computerized SystemA process or operation integrated with a computer system.

ContaminationThe undesired introduction of impurities of a chemical or microbiologicalnature, or of foreign matter, into or onto a raw material, intermediate, or


API during production, sampling, packaging or repackaging, storage ortransport.

Contract ManufacturerA manufacturer performing some aspect of manufacturing on behalf of theoriginal manufacturer.

CriticalDescribes a process step, process condition, test requirement, or other rel-evant parameter or item that must be controlled within predeterminedcriteria to ensure that the API meets its specification.

Cross-ContaminationContamination of a material or product with another material or product.

DeviationDeparture from an approved instruction or established standard.

Drug (Medicinal) ProductThe dosage form in the final immediate packaging intended for marketing(Reference Q1A).

Drug SubstanceSee Active Pharmaceutical Ingredient.

Expiry Date (or Expiration date)The date placed on the container/labels of an API designating the timeduring which the API is expected to remain within established shelf-lifespecifications if stored under defined conditions, and after which it shouldnot be used.

ImpurityAny component present in the intermediate or API that is not the desiredentity.

Impurity ProfileA description of the identified and unidentified impurities present in anAPI.

In-Process Control (or Process Control)Checks performed during production in order to monitor and, if appro-priate, to adjust the process and/or to ensure that the intermediate or APIconforms to its specifications.

IntermediateA material produced during steps of the processing of an API that under-goes further molecular change or purification before it becomes an API.Intermediates may or may not be isolated. (Note: this Guide only addresses


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those intermediates produced after the point that the company has definedas the point at which the production of the API begins.)

LotSee Batch.

Lot NumberSee Batch number.

ManufactureAll operations of receipt of materials, production, packaging, repackaging,labelling, relabelling, quality control, release, storage, and distribution ofAPIs and related controls.

MaterialA general term used to denote raw materials (starting materials, reagents,solvents), process aids, intermediates, APIs and packaging and labellingmaterials.

Mother LiquorThe residual liquid which remains after the crystallization or isolation pro-cesses. A mother liquor may contain unreacted materials, intermediates,levels of the API and/or impurities. It may be used for further processing.

Packaging MaterialAny material intended to protect an intermediate or API during storageand transport.

ProcedureA documented description of the operations to be performed, the precau-tions to be taken and measures to be applied directly or indirectly relatedto the manufacture of an intermediate or API.

Process AidsMaterials, excluding solvents, used as an aid in the manufacture of anintermediate or API that do not themselves participate in a chemical orbiological reaction (e.g. filter aid, activated carbon, etc.).

Process ControlSee In-Process Control.

ProductionAll operations involved in the preparation of an API from receipt ofmaterials through processing and packaging of the API.

QualificationAction of proving and documenting that equipment or ancillary systemsare properly installed, work correctly, and actually lead to the expected


results. Qualification is part of validation, but the individual qualificationsteps alone do not constitute process validation.

Quality Assurance (QA)The sum total of the organised arrangements made with the object of ensur-ing that all APIs are of the quality required for their intended use and thatquality systems are maintained.

Quality Control (QC)Checking or testing that specifications are met.

Quality Unit(s)An organizational unit independent of production which fulfills both Qual-ity Assurance and Quality Control responsibilities. This can be in the formof separate QA and QC units or a single individual or group, dependingupon the size and structure of the organization.

QuarantineThe status of materials isolated physically or by other effective means pend-ing a decision on their subsequent approval or rejection.

Raw MaterialA general term used to denote starting materials, reagents, and solventsintended for use in the production of intermediates or APIs.

Reference Standard, PrimaryA substance that has been shown by an extensive set of analytical teststo be authentic material that should be of high purity. This standard canbe: (1) obtained from an officially recognised source, or (2) prepared byindependent synthesis, or (3) obtained from existing production material ofhigh purity, or (4) prepared by further purification of existing productionmaterial.

Reference Standard, SecondaryA substance of established quality and purity, as shown by comparisonto a primary reference standard, used as a reference standard for routinelaboratory analysis.

ReprocessingIntroducing an intermediate or API, including one that does not conformto standards or specifications, back into the process and repeating a crystal-lization step or other appropriate chemical or physical manipulation steps(e.g., distillation, filtration, chromatography, milling) that are part of theestablished manufacturing process. Continuation of a process step after an


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in-process control test has shown that the step is incomplete is consideredto be part of the normal process, and not reprocessing.

Retest DateThe date when a material should be re-examined to ensure that it is stillsuitable for use.

ReworkingSubjecting an intermediate or API that does not conform to standards orspecifications to one or more processing steps that are different from theestablished manufacturing process to obtain acceptable quality intermedi-ate or API (e.g., recrystallizing with a different solvent).

Signature (signed)See definition for signed.

Signed (signature)The record of the individual who performed a particular action or review.This record can be initials, full handwritten signature, personal seal, orauthenticated and secure electronic signature.

SolventAn inorganic or organic liquid used as a vehicle for the preparationof solutions or suspensions in the manufacture of an intermediate orAPI.

SpecificationA list of tests, references to analytical procedures, and appropriate accep-tance criteria that are numerical limits, ranges, or other criteria forthe test described. It establishes the set of criteria to which a materialshould conform to be considered acceptable for its intended use. “Con-formance to specification” means that the material, when tested accord-ing to the listed analytical procedures, will meet the listed acceptancecriteria.

ValidationA documented program that provides a high degree of assurance that a spe-cific process, method, or system will consistently produce a result meetingpre-determined acceptance criteria.

Validation ProtocolA written plan stating how validation will be conducted and defining accep-tance criteria. For example, the protocol for a manufacturing process iden-tifies processing equipment, critical process parameters/operating ranges,product characteristics, sampling, test data to be collected, number of val-idation runs, and acceptable test results.


Yield, ExpectedThe quantity of material or the percentage of theoretical yield anticipatedat any appropriate phase of production based on previous laboratory, pilotscale, or manufacturing data.

Yield, TheoreticalThe quantity that would be produced at any appropriate phase of produc-tion, based upon the quantity of material to be used, in the absence of anyloss or error in actual production.

CHAPTER

3

UK Guidance on Manufacture

Contents

Manufacturers’ Obligations 272Qualified Persons 275General 275Code of Practice for Qualified

Persons in the PharmaceuticalIndustry 276

1.0 Introduction 2762.0 Regulatory Basis for the Qualified

Person 2773.0 Purpose of the Code 2774.0 Application of the Code 2785.0 Terminology 2786.0 General Principles 2797.0 Routine Duties of a Qualified

Person 2808.0 Performance of Duties and

Regulatory Compliance 2829.0 Number and Location of Qualified

Persons 28310.0 Contracted Qualified

Persons 28311.0 Contract Manufacture and/or

Testing 28412.0 Continuing Professional

Development 28513.0 Professional Conduct 28614.0 Disciplinary Procedures 287

Appendix 1: UK Statements onCPD 287

Import from Third Countries 290Mutual Recognition Agreements on

Good Manufacturing Practice(GMP) and ManufacturingAuthorisation 290

Content of the Fabricator’s/Manufacturer’s Batch Certificatefor Drug/Medicinal ProductsExported to Countries Under theScope of a Mutual RecognitionAgreement (MRA) 291

UK Guidance on Certificates ofAnalysis 292

GMP for Starting Materials 293Manufacture and Importation of

Unlicensed Medicines for HumanUse 294

Introduction 294Manufacture and supply of unlicensed

relevant medicinal products forindividual patients (“specials”) 294

Importation and supply of unlicensedrelevant medicinal products forindividual patients 295

Contact 296

271


Manufacturers’ Obligations

The holder of a manufacturer’s licence must comply with certain obliga-tions in relation to the manufacture and assembly of relevant medicinalproducts. These obligations are set out in Regulation 2 of The Medicinesfor Human Use (Manufacturing, Wholesale Dealing and MiscellaneousAmendments) Regulations 2005 [SI 2005 No. 2789]. They require thatthe licence holder shall:

(a) comply with the principles of good manufacturing practice;(b) only use active starting materials which have been manufactured or

assembled in accordance with good manufacturing practice, unless theyare for use in an exempt medicinal product;

(c) maintain such staff, premises, equipment and facilities necessary toconduct the manufacture and assembly of relevant medicinal productsin accordance with the requirements of their manufacturer’s licenceand the marketing authorizations of the medicinal product beingmanufactured;

(d) maintain such staff, premises, equipment and facilities for the handling,control, storage and distribution of the relevant medicinal productsmanufactured or assembled in accordance with their manufacturer’slicence as necessary to maintain the quality of those medicinal products;

(e) ensure that any arrangements made for the control, storage and distri-bution of the relevant medicinal products are adequate to maintain thequality of those products;

(f) not carry out any manufacture or assembly of medicinal products otherthan in accordance with their manufacturer’s licence and at the premisesspecified in the licence;

(g) not use any premises for the handling, control, storage or distributionof relevant medicinal products other than those named on their manu-facturer’s licence which have been approved by the licensing authorityfor that purpose;

(h) inform the licensing authority before making any material alterationto the premises or facilities used under their manufacturer’s licence, orin the operations for which they are used;

(i) inform the licensing authority of any proposed changes to any per-sonnel named in their manufacturer’s licence as responsible for qualitycontrol, including the person named as the qualified person;

(j) permit the licensing authority to carry out inspections, take samples orcopies of documentation as necessary to enable the licensing authorityto ascertain whether there are any grounds for suspending, revokingor terminating the manufacturer’s licence or to verifying any statementcontained in an application for a licence;

(k) ensure that any blood or blood component that they import into theUnited Kingdom and use as a starting material or raw material in the


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manufacture of a relevant medicinal product meets equivalent stan-dards of quality and safety to those laid down in Commission Directive2004/33/EC, implementing Directive 2002/98/EC of the European Par-liament and of the Council as regards certain technical requirementsfor blood and blood components.

(l) ensure that he has at all times at his disposal the services of at leastone qualified person who is responsible for carrying out, in relation tothe medicinal products being manufactured or assembled, the dutiesspecified in Article 51 of the Directive 2001/83/EC as amended. (SeeSection 8).

Where the manufacturer’s licence holder distributes the relevant medicinalproduct manufactured or assembled in accordance with the manufacturer’slicence he shall:

� comply with the principles of good distribution practice;� ensure the appropriate and continued supply of the medicinal product

that he manufactures or assembles;� sell only, or offer for sale or supply, the medicinal product in accordance

and conformity with a marketing authorization unless it is an exemptmedicinal product or is distributed to another Member State where itcan be legally used as an unlicensed relevant medicinal product in theMember State concerned;

� distribute only their medicinal products to a holder of a wholesaledealer’s licence relating to those products; a holder of an authorizationgranted by the competent authority of another EEA State authorising thesupply of those products by way of wholesale dealing; any person whomay lawfully sell those products by retail or who may lawfully supplythem in circumstances corresponding to retail sale; or any person whomay lawfully administer those products;

� where the relevant medicinal product is supplied to a person for retailsale or supply, the manufacturer’s licence holder must enclose with theproduct a document which makes it possible to ascertain the date onwhich the supply took place; the name and pharmaceutical form ofthe product supplied; the quantity of product supplied; and the namesand addresses of the person or persons from whom the products weresupplied.

The Standard Provisions are incorporated into all manufacturer’s licencesin the form set out in Schedule 1 of the “Manufacturing and WholesaleDealing Regulations”, that is, those provisions which may be included inall licences unless an individual licence provides variations to them. Theyrequire that the manufacturer’s licence holder shall:

(a) place their quality control system referred to in Article 11(1) of Com-mission Directive 2003/94/EC under the authority of the head of theQuality Control (QC);


(b) provide information about the products being manufactured or assem-bled under their manufacturer’s licence and about the operations beingconducted in relation to such manufacture or assembly as may berequested by the licensing authority;

(c) inform the licensing authority of any proposed changes to be made toany personnel named in his licence, responsible for supervising the pro-duction operations; in charge of the animals from which are derivedany substances used in the production of the medicinal products beingmanufactured or assembled; or responsible for the culture of any liv-ing tissues used in the manufacture of the medicinal products beingmanufactured or assembled;

(d) keep readily available for inspection by a person authorised by thelicensing authority the batch documentation referred to in Article 9(1)of Commission Directive 2003/94/EC, and permit that person to takecopies or make extracts from such documentation;

(e) keep readily available for examination by a person authorised bythe Licensing Authority, samples of each batch of finished relevantmedicinal product referred to in Article 11(4) of Commission Directive2003/94/EC;

(f) withhold any batch of any medicinal product from sale or export so faras may be reasonably practicable for up to 6 weeks when informed thatit does not comply with its licence specifications or with the provisionsof the Act or of any regulations under the Act;

(g) ensure that any tests for determining conformity with the standards andspecifications applying to any particular product used in the manufac-ture of a medicinal product shall, except so far as the conditions of theproduct specification for that product otherwise provide, be applied tosamples taken from the medicinal product after all manufacturing pro-cesses have been completed, or at such earlier stage in the manufactureas may be approved by the licensing authority;

(h) where the manufacturer’s licence relates to the assembly of any relevantmedicinal product or class of product, and the licence holder suppliesthat relevant medicinal product at such a stage of assembly that doesnot fully comply with the provisions of the product specification thatrelate to labelling, the licence holder shall communicate the particularsof those provisions to the person to whom that product has been sosupplied;

(i) where the manufacturer’s licence relates to the assembly of a relevantmedicinal product; and that medicinal product is not manufactured bythe licence holder; and particulars as to the name and address of themanufacturer of, or of the person who imports, that relevant medicinalproduct have been given by the licence holder to the licensing author-ity, the licence holder shall forthwith notify the licensing authority inwriting of any changes in such particulars;


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(j) keep readily available for examination by a person authorised by thelicensing authority durable records of the details of manufacture ofany intermediate products held by him which are for use in the manu-facture of biological medicinal products for human use and shall bein such form as to ensure that the manufacturer’s licence holder has acomprehensive record of all matters that are relevant to an evaluationof the safety, quality and efficacy of any finished biological medicinalproduct for human use which he manufactures using those intermediateproducts. The records shall not be destroyed without the consent of thelicensing authority until the records of the details of manufacture ofany finished medicinal products which were or may be manufacturedusing those intermediate products may be destroyed in accordance withthe requirements of these Regulations;

(k) arrange for animals which are used in the production of any medicinalproducts, to be housed in premises of such a nature, and be managed insuch a manner, as to facilitate compliance with the provisions relatingto them in the relevant marketing authorizations;

(l) take all reasonable precautions and exercise all due diligence to ensurethat any information he provides to the licensing authority which isrelevant to an evaluation of the safety, quality or efficacy of any medi-cinal product for human use which he manufactures or assembles; orany starting materials or intermediate products that he holds which arefor use in the manufacture of relevant medicinal products, is not falseor misleading in any material particular.

The manufacturer’s licence holder may use a contract laboratory pursuantto Article 11(2) of Commission Directive 2003/94/EC if operated by aperson approved by the licensing authority, i.e. if not on the manufacturer’slicence a contract laboratory will not be acceptable1.

For any changes to the information shown on a licence, prior approvalfrom the licensing authority must be obtained.

Qualified Persons

General

All holders of a manufacturer’s licence for licensed products, includingfor the purposes of import, are required to have available the servicesof a Qualified Person (QP), who must be named on the licence. Whenconsidering a nomination, the licensing authority (the MHRA) routinelytakes into account the assessment of the nominee’s eligibility made by the

1 A contract laboratory is required to be named on the manufacturer’s licence.


joint assessment panel of the Institute of Biology, the Royal PharmaceuticalSociety of Great Britain and the Royal Society of Chemistry. Exceptionally,the MHRA will assess a nominee directly if he or she is not a member ofany of these professional bodies.

Title IV of Directive 2001/83/EC as amended lays down the require-ments for QPs in relation to products for human use. Article 51 definesthe duties of the QP; Articles 49 and 50 define the requirements for eligi-bility under the permanent and transitional arrangements respectively, andArticle 52 requires Member States to ensure that the duties of QPs are ful-filled, either through administrative measures or by making such personssubject to a professional code of conduct. Title IV of Directive 2001/82/ECas amended lays down equivalent requirements in relation to veterinaryproducts. Guidance on the duties of QPs is given in the EU Guide to GMPand in particular in its Annex 16.

By inspection and other means the licensing authority routinely assesseswhether or not QPs are fulfilling their duties. In making this assessment,reference is made to the Code of Practice for Qualified Persons producedjointly by the Institute of Biology, the Royal Pharmaceutical Society ofGreat Britain and the Royal Society of Chemistry in collaboration with theMHRA and the Veterinary Medicines Directorate. This reference is madewhether or not the QP in question is a member of one or more of thesebodies (see next section).

All QPs should be guided in fulfilling their duties by the Code of Prac-tice, although the references in Sections 11.1 and 12.4 to the disciplinarymachinery of the professional bodies, and in Section 11.6 to the advicewhich professional bodies can give, would not be relevant in the case of aQP who is not a member of one of these bodies. The European IndustrialPharmacists Group adopted a similar code2 in 1995 for the guidance of itsmembers.

Code of Practice for Qualified Persons in the Pharmaceutical Industry

1.0 Introduction

1.1 The concept of the Qualified Person (QP), first established in 1975, isa unique regulatory requirement that applies only within the EuropeanUnion (EU). The only comparable situation exists within Member Statesof the European Economic Area (EEA) with whom the EU has reciprocalagreements.

2 European Industrial Pharmacists Group (est. June 1966). Code of Practice forQualified Persons. Available from the Industrial Pharmacists Group of the RoyalPharmaceutical Society of Great Britain.


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1.2 Each holder of an Authorisation to Manufacture products for use in a Clin-ical Trial or products subject to Marketing Authorisations, within MemberStates of the EU, must name a person or persons who are eligible to act inthe capacity of QP.

1.3 The requirement for QP covers both Human and Veterinary MedicinalProducts including those intended for export.

1.4 Particular conditions for formal qualifications and practical experience foreligibility to act as a QP are specified in the relevant EU Council Directives(see 2 below). Ensuring compliance with these conditions is the responsi-bility of the Competent Authorities of the Member States.

1.5 The primary legal responsibility of the QP is to certify batches of Medi-cinal Product prior to use in a Clinical Trial (Human Medicinal Productsonly) or prior to release for sale and placing on the market (Human andVeterinary Medicinal Products). However, the wider technical, ethical andprofessional obligations in terms of patient Safety, Quality and Efficacymust also be considered. Hence this professional Code of Practice, whichis designed to take account of these issues.

2.0 Regulatory Basis for the Qualified Person

For ease of reference the key regulatory documents concerning the QP areas follows:

(i) Principles and Guidelines of Good Manufacturing Practice for Medi-cinal Products for Human Use: Directive 2003/94/EC Article 7.

(ii) Principles and Guidelines of Good Manufacturing Practice for Veteri-nary Medicinal Products: Directive 91/412/EEC Article 7.

(iii) Good Clinical Practice in the Conduct of Clinical Trials on MedicinalProducts for Human Use: Directive 2001/20/EC Article 13.

(iv) Community Code Relating to Veterinary Medicinal Products: Direc-tive 2001/82/EC - Title IV - Manufacture and Imports Articles 44–57.

(v) Community Code Relating to Medicinal Products for Human Use:Directive 2001/83/EC Title IV Manufacture and Importation Articles40–53.

(vi) Good Manufacturing Practices: Eudralex Volume 4

Annex 13: Manufacture of Investigational Medicinal ProductsAnnex 16: Certification by a Qualified Person and Batch Release

3.0 Purpose of the Code

3.1 The legal functions of the Qualified Person (QP) are stated in Article 51of Directive 2001/83/EC or Article 55 of Directive 2001/82/EC and repro-duced in the preface to the UK Joint Professional Bodies’ Study Guide 2000.


3.2 The aims and objectives of the Code of Practice are to provide operationalguidelines for carrying out the functions of the Qualified Person withina professional code of conduct in accordance with Article 56 of CouncilDirective 2001/82/EC and/or Article 52 of Council Directive 2001/83/EC.

3.3 The Code is in the interests of Qualified Persons, their employers, patientsand the Competent Authorities of the Member States.

4.0 Application of the Code

4.1 The Code is equally applicable to Qualified Persons who have achievedthat status under the transitional arrangements, and under the permanentprovisions.

4.2 Qualified Persons have a professional duty to decline to act as QualifiedPersons in the release of product types for which they do not possess therelevant experience and knowledge.

4.3 It should be noted that Qualified Persons are eligible to certify batches ofmedicinal product as follows:

(i) those who have achieved Qualified Person status under the perma-nent provisions are eligible to certify batches of human or veterinarymedicinal products in any member state within the European Union(EU);

(ii) those who have achieved Qualified Person status under the transi-tional arrangements for human medicines are eligible to certify batchesof human or veterinary medicinal products, and such certification isrestricted to acting in the United Kingdom (UK) although such prod-ucts, once certified, can legally be sold or supplied throughout the EU;

(iii) those who have achieved Qualified Person status under the transi-tional arrangements for veterinary medicines are only eligible to cer-tify batches of veterinary medicinal products, and such certification isrestricted to acting in the UK although such products, once certified,can legally be sold or supplied throughout the EU.

4.4 The Code applies equally to Qualified Persons involved in human and/orveterinary medicines.

4.5 The Licensing Authority may refer to this Code in connection with disci-plinary proceedings against a Qualified Person under Article 52 of Directive2001/83/EC or Article 56 of Directive 2001/82/EC.

5.0 Terminology

5.1 The terminology used in this Code of Practice corresponds with thatused in the current versions of the EC directives on Good Pharmaceutical


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Manufacturing Practice (GMP) and the Guide to Good PharmaceuticalManufacturing Practice.

5.2 Within the EU the terms Marketing Authorisation, Manufacturing Autho-risation and Investigational Medicinal Products Authorisation are gener-ally used and shall henceforth be referred to throughout this Code.

The UK licensing system currently uses the equivalent terms ProductLicence (= Marketing Authorisation) and Manufacturer’s Licence (= Man-ufacturing Authorisation).

6.0 General Principles

6.1 Pharmaceutical Manufacturers and the Competent Authorities of theMember States have a duty to ensure that patients are properly protectedand that medicinal products meet appropriate requirements for safety, qual-ity and efficacy.

6.2 The legal framework is provided by the European Directives and “TheRules Governing Medicinal Products in the European Union”, which areimplemented by individual Member States’ national legislation.

6.3 An operational framework is provided in the current Volume 4 of the RulesGoverning Medical Products in the European Union “Good ManufacturingPractices”. In Chapter 1 of the Guidelines, Quality Management, it statesthat:

“The holder of a Manufacturing Authorisation must manufacture medici-nal products so as to ensure that they are fit for their intended use, complywith the requirements of the Marketing Authorisation and do not placepatients at risk due to inadequate safety, quality or efficacy. The attain-ment of this quality objective is the responsibility of senior managementand requires the participation and commitment by staff in many differentdepartments and at all levels within the company, the company’s suppliersand the distributors.

To achieve the quality objective reliably there must be a comprehen-sively designed and correctly implemented system of Quality Assuranceincorporating Good Manufacturing Practice and thus Quality Control. Itshould be fully documented and its effectiveness monitored. All parts of theQuality Assurance system should be adequately resourced with competentpersonnel, and suitable and sufficient premises, equipment and facilities.There are additional legal responsibilities for the holder of the Manufac-turing Authorisation and for the Qualified Person(s).

The basic concepts of Quality Assurance, Good Manufacturing Practiceand Quality Control are inter-related. They are described here in orderto emphasise their relationships and their fundamental importance to theproduction and control of medicinal products.”


6.4 Qualified Persons should be aware that whilst Quality Management appliesto full-scale manufacture, it also extends to original product design, devel-opment, formulation and preparation of medicinal products for use inclinical trials. This includes the establishment of well-defined manufac-turing processes, sampling programmes and analytical tests methods andappropriate specifications for ingredients, printed and unprinted packagingcomponents and finished dosage forms.

7.0 Routine Duties of a Qualified Person

Qualified Persons have routine duties, some of which may be delegated (seelater), in line with the above general principles. Before certifying a batchprior to release the Qualified Person doing so should always ensure thatthe following requirements have been met:

“The meaning of the word ensure in this context is that the QualifiedPerson must be confident that various actions, which may not be underhis/her direct control, have in fact been taken.” See also Section 8.

7.1 The Marketing Authorisation and Manufacturing Authorisation or Investi-gational Medicinal Products Authorisation requirements for the MedicinalProducts have been met for the batch concerned.

7.2 The principles and guidelines of GMP as stated in Directive 2003/94/EC(Human) or Directive 91/412/EEC (Veterinary) and as interpreted in theEU Guide to GMP have been followed.

7.3 The principal manufacturing and testing processes have been validated.

7.4 All the necessary quality control checks and tests have been performed, andaccount taken of the manufacturing and packaging conditions including areview of batch records. The EU Guide to GMP suggests that the Headof Production and the Head of Quality Control assume line managementresponsibilities for these activities.

7.5 Any changes or deviations in manufacturing, packaging or quality con-trol have been notified in accordance with a well-defined reporting systembefore any product batch is released. Such changes may need notificationto and approval by the Competent Authorities of the Member States.

7.6 Any additional sampling, inspection, tests and checks have been carriedout or initiated, as appropriate, to cover changes or deviations.

7.7 All necessary manufacturing, packaging and associated documentation hasbeen completed and endorsed by suitably authorised staff trained in theconcept of Quality Assurance and Good Manufacturing Practices.

7.8 Regular audits, self-inspections and spot checks are being carried out byexperienced staff.


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7.9 All relevant factors have been considered including any not specificallyassociated with the output batch directly under review (e.g. calibrationand maintenance records, environmental monitoring).

7.10 The legal requirements regarding imported products have been fully met.For products imported from outside the EU or EEA, the Qualified Personshould ensure testing within the EU/EEA to the requirements of the Mar-keting Authorisation and any other tests to assure quality of the products,unless a mutual recognition agreement between the EU and the third coun-try concerned allows the acceptance of manufacturer’s batch certificationin lieu.

The Qualified Person should also be satisfied that the medicinal prod-ucts have been manufactured in accordance with GMP standards whichare equivalent to those of the EU or EEA.

7.11 The Qualified Person should also recognise the need to consult other com-pany experts in the various areas of the Study Guide to reinforce his/herknowledge on appropriate points when a doubtful situation arises (e.g.stability, unusual analytical results, process or equipment changes, poten-tial environmental or microbiological risks, re-labelling, abnormal yields,cross contamination risks etc.).

7.12 To maintain a register (or equivalent document) as a record of productbatches certified by the Qualified Person prior to batch release.

7.13 To retain reference samples of each product batch at the site of manufacturefor a period of time in compliance with EU regulations and the LicensingAuthority’s requirements.

7.14 In considering how to perform the above duties, 7.1 to 7.13, the QualifiedPerson will have to take account of the nature and size of the operationsbeing performed. For example, in a very small company with a limitedrange of products it may be possible that the Qualified Person can takedirect responsibility for some or all of the tasks outlined above. In largerorganisations, the Qualified Person will be dependent upon the knowledgeand expertise of his/her colleagues in undertaking some or all of the tasks.

However, it is of paramount importance that the Qualified Person takessteps, within a well planned Quality Management System, to assure himselfor herself that the tasks allocated are in fact being performed satisfactorily.Hence the routine duties of the Qualified Person depend very much upona team effort wherein the individuals concerned realise the position andresponsibility of the Qualified Person and provide every support.

What cannot be over emphasised in this context is the Qualified Per-son’s commitment to meet regularly with professional colleagues in allfunctional groups and to understand their contribution and impact uponquality.


The certification of a batch prior to release must be performed by aQualified Person.

8.0 Performance of Duties and Regulatory Compliance

8.1 Management, as a requirement of Quality Assurance, should clearly definethe areas of work and the method of operating in the absence of the regularQualified Person.

In the absence of one Qualified Person, the task of certifying batches canonly be delegated to another Qualified Person nominated on the Manu-facturing Authorisation and who is knowledgeable and experienced withregard to the medicinal products under review.

8.2 Whilst each Qualified Person has a personal and professional responsibilityfor being certain that the various checks and tests have been carried out,the detail of this work is described in the EU Guide to GMP as normallythe responsibility of the Head of Production and the Head of Quality Con-trol who must ensure that appropriately trained and experienced staff areavailable.

Ultimately the Qualified Person must be satisfied either directly or, moreusually, by the proper operation of quality systems, which include appro-priate approvals, audits, self inspections and spot checks that manufac-turing, packaging and quality control testing have complied with relevantrequirements.

Batch certification without such adequate steps may be regarded asprofessional misconduct.

8.3 It must be recognised that the Qualified Person depends upon many ofhis/her working colleagues for the achievement of quality and regulatorycompliance in the manufacture of medicinal products. It is therefore ofparamount importance that he or she achieves a good working relationshipwith other persons in positions of responsibility. These are likely to includethose responsible for:

� processing and packing operations� quality control laboratories� validation� application and maintenance of Manufacturing and Marketing Autho-

risations� provision of engineering services� procurement of starting and packaging materials� storage, transport and distribution� contract services.

8.4 It is recommended that the company and the Qualified Person take thenecessary steps to appraise other functional groups, and the responsible


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people who belong to them, of the role of the Qualified Person within thecompany and how they should give proper support.

8.5 Ensuring compliance with the conditions of the Marketing Authorisationis a primary duty of the Qualified Person. It is, therefore, essential that theQualified Person has access at all times to the dossiers upon which Market-ing Authorisations have been granted, including any variations affectingsuch approval. The control of change needs to be rigorously monitoredby the Qualified Person especially where there are implications for compli-ance, quality and patient safety. Particular attention needs to be paid to thiswhen the manufacturer is making products for a Marketing Authorisationholder in a different company.

8.6 The Qualified Person should be present at the manufacturing site for asufficient proportion of the working time in order to discharge the legaland professional obligations outlined in this Code and to ensure the properoperation of a Quality Management System including the control of anydelegated duties.

8.7 Manufacturing Authorisations contain the names of the persons respon-sible for Production, Quality Control, and the name(s) of the QualifiedPerson(s). The duties of these members of staff must be clear in their respec-tive job descriptions and they must have the authority required under therelevant EC directives.

9.0 Number and Location of Qualified Persons

9.1 The provisions in Article 52 of Council Directive 2001/82/EC and/or Arti-cle 48 of Council Directive 2001/83/EC and the principles outlined in theEU Guide to GMP for Medicinal Products only require a company ororganisation to nominate one person on a Manufacturing Authorisationto carry out the duties of the Qualified Person provided that person is atthe disposal of the company at all times and can carry out the requiredfunctions.

9.2 Some organisations may have a complex structure, or operate at severallocations, or both, which would make it necessary, where justified, to nom-inate several Qualified Persons on its Manufacturing Authorisation.

10.0 Contracted Qualified Persons

10.1 In a number of cases, especially with smaller companies, a “ContractedQualified Person” provides the service. In such cases the duties and respon-sibilities of a “Contracted Qualified Person” are the same as those QualifiedPersons who are permanently employed by their company; the QP is notan employee of the company but provides his services under contract.


The term “Contracted Qualified Person” is not a formal title and is usedonly in the sense of a Qualified Person providing an independent serviceunder contract to a company.

10.2 In addition to compliance with the provisions applicable to all QualifiedPersons including all the routine duties outlined in this Code of Practice,Contracted Qualified Persons should observe the following:

� have a clear written contract which delineates the duties and responsi-bilities of the Qualified Person – as agreed between the company andthe “Contracted Qualified Person”. Both should sign and retain a copyof the contract;

� be readily available to the staff of the company for advice and discus-sion, and also be present during regulatory inspections and involved incommunications with the inspectors;

� ensure that the company to whom the services are provided will allowfree access to any people, information, documentation, premises, pro-cedures etc. which are relevant to the decision-making processes whencertifying batches for sale. In addition the company should inform theQualified Person of any deviations which need to be considered in rela-tion to batch certification. Such deviations should be provided to theQualified Person promptly and in writing;

� ensure that sufficient spot checks, inspections, and audits of the company(whether in the EU or overseas) are carried out; in particular the “Con-tracted Qualified Person” should satisfy himself/herself that an effectivepharmaceutical Quality Management System is being operated.

10.3 Particularly for smaller companies, the person acting as contracted QPmay agree with the company to provide some of the necessary servicessuch as, for example, staff training, internal audits and maintenance ofauthorisations, personally in addition to performing strictly QP duties.

10.4 If any doubt exists concerning the duties and responsibilities between theQualified Person and the company who requires his/her services, it is rec-ommended that he or she should contact their local Regulatory Inspectoror their professional body for advice.

10.5 This Code of Practice should be brought to the attention of the ChiefExecutive Officer of the company who wishes to have the services of a“Contracted Qualified Person”.

11.0 Contract Manufacture and/or Testing

11.1 Where products are manufactured and/or packed under contract thereshould be a clearly written technical agreement between the contract giver


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and the contract acceptor. Such an agreement should be reviewed andapproved by the Qualified Person engaged by the contract giver and accep-tor. The agreement should clearly delineate the areas and responsibilitiesof both Qualified Persons.

11.2 The contract acceptor, who normally will be required to hold a manufac-turing authorisation, may accept full responsibility for batch certificationprovided that the Qualified Person has all the appropriate information(including access to relevant details in the Marketing Authorisation(s))and authority to fulfil these duties. Nevertheless the decision concerningresponsibility for batch certification remains a matter between contractgiver and acceptor depending on the circumstances.

11.3 The provisions in 11.1 apply equally to the testing of samples under con-tract. The contract testing laboratory may not hold its own manufacturingauthorisation but in this case must be authorised on the contract giver’sauthorisation.

12.0 Continuing Professional Development

12.1 Qualified Persons have a personal and professional duty to keep theirknowledge and experience up to date (Annex 16, item 8.3, EU Guideto GMP, Volume 4 of “The Rules Governing Medicinal Products in theEuropean Union”). It is expected that this would cover the current state ofpharmaceutical quality management, regulatory aspects and GMP guide-line standards, product manufacturing and control technology, and generalwork practices.

12.2 Records of Continuing Professional Development (CPD) should be kept toreflect this important longer-term aspect of the Qualified Person’s continuedperformance of professional duties.

12.3 Attention is drawn to the individual Member State’s statements on CPD,which underline the importance of this aspect of a Qualified Person’s per-formance of duties. These statements appear as Appendix 1 to this Code,and they will also be of value to those Qualified Persons who are not mem-bers of any of the three professional bodies.

12.4 In the event of a Qualified Person making a major change in job responsibil-ities, for example from a company making only sterile dosage forms to onewith a wider range of products including solid dose forms, the QualifiedPerson and the senior management of the company involved should recog-nise the need for additional education and training and take adequate stepsto demonstrate that proper provision is made for this. Such extra trainingshould be undertaken before the Qualified Person acts in a new situation.


13.0 Professional Conduct

13.1 Qualified Persons are subject to the overall jurisdiction of the Bye-laws,Charters and Regulations, Codes of Conduct, Disciplinary Regulationsand any general guidelines of their own professional body, and shouldhave access to them.

13.2 Qualified Persons have duties not only to their employer but also to theCompetent Authorities of the Member States and its inspection service.They must ensure that appropriate senior company executives are madefully aware of any manufacturing and/or testing difficulties which maycast doubt on the certification of batches or post facto might require aproduct recall.

13.3 If there is any aspect of the Quality Assurance system which is not inaccordance with the Directives and Guidelines for Good ManufacturingPractice then the Qualified Person has a duty to bring this to the attentionof Senior Management and ensure that appropriate corrective measuresare taken.

13.4 Qualified Persons should establish a good working relationship with Regu-latory Inspectors and as far as possible provide information on requestduring site inspections.

NB. There may be situations outside of site inspections where the Qual-ified Person may wish to consult with the local Regulatory Inspector foradvice or clarification in particular circumstances with which the QualifiedPerson is faced.

13.5 The following assumption is made by the professional bodies acting jointlywhen certifying the eligibility of a Qualified Person:

� in co-operation with their employers, Qualified Persons will undertakeContinuing Professional Development to maintain and extend their tech-nical and professional competence. (See also Section 12.0 above.)

13.6 The following assumptions are made, firstly by the professional bodiesacting jointly when certifying the eligibility of a Qualified Person and,secondly, by the Competent Authority when accepting an eligible QualifiedPerson for nomination on a Manufacturing Authorisation:

� in cases where undue pressures to depart from professional obliga-tions cannot be counterbalanced by reference to this and other rele-vant Codes of Practice, Qualified Persons, preferably having informedtheir employer first, should consult the appropriate professional bodyfor confidential advice.

� management has a duty to provide Qualified Persons with appropri-ate resources and to ensure that Quality Management Systems and


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communications are working effectively. Therefore, Qualified Personsalso have a duty to make representations to management, if necessary inwriting, whenever standards appear to be falling short of Good Manu-facturing Practice(s). This duty should be reflected by appropriate word-ing in the Qualified Person’s job description.

14.0 Disciplinary Procedures

14.1 Article 56 of Council Directive 2001/82/EC and Article 52 of CouncilDirective 2001/83/EC. read inter alia:

“Member States shall ensure that the duties of Qualified Persons . . . arefulfilled, either by means of appropriate administrative measures or bymaking such persons subject to a professional Code of Conduct.

Member States may provide for the temporary suspension of such a per-son upon the commencement of administrative or disciplinary proceduresagainst him for failure to fulfil his obligations.”

If it were found that a QP had certified in a register or equivalent documenta product batch as fit for sale without ensuring that the relevant tests andchecks had been carried out, this failure might be a matter for considerationby the appropriate professional body to which he/she might belong as amatter of professional misconduct.

14.2 The UK professional bodies have established disciplinary procedures todeal with cases of possible misconduct. One of the powers is to remove thename of an individual from the appropriate register or registers and theywill act together as appropriate in the case of a Qualified Person who is amember of two or three of the Societies. In such cases, professional bodieswill inform the Competent Authority.

14.3 The Member State Competent Authority is the body with the power todelete the Qualified Person’s name from the Manufacturing Authorisation.

Appendix 1: UK Statements on CPD

INSTITUTE OF BIOLOGY

CONTINUING PROFESSIONAL DEVELOPMENT STATEMENT

In common with many other professional biologists, Qualified Personswork in a changing scientific, commercial and regulatory environment. Thisrequires individuals to commit themselves to updating their knowledge andskills in order to maintain their competence to do the job. Increasingly,there is a demand from employees undertaking such development to have


it recognised, and for employers to be able to demonstrate the competenceof their employees to regulatory bodies, their customers and the generalpublic. Continuing Professional Development (CPD) emphasises qualityand confers a competitive edge.

The Institute of Biology has, therefore, placed a high priority on thedevelopment of a Continuing Professional Development scheme, to ensurethat chartered biologists keep up to date and maintain their competence.The Institute is in the process of carrying out a pilot CPD scheme basedon national occupational standards for professional biologists developedby the Science, Technology and Mathematics Council. The CPD schemehas been designed as a benefit and to support members in advancing self-education whilst also underpinning professional competence.

The scheme focuses on the demonstration of work place competencemaintained by informal and formal activities, such as reading, conferenceattendance and short courses. The scheme initially is voluntary.

ROYAL PHARMACEUTICAL SOCIETY OF GREAT BRITAIN


The Royal Pharmaceutical Society of Great Britain (RPSGB) seeks to safe-guard and promote the interests of the public and the profession by identi-fying the fundamental role and accountability of pharmacists. Pharmacistsmust keep up to date with changes in pharmacy practice, the law relatingto pharmacy and the knowledge and technology applicable to pharmacy,and to maintain competence and effectiveness as a practitioner.

The “key responsibilities of a pharmacist” are set out in the RPSGB’sCode of Ethics.

The Code of Ethics states that practising pharmacists are expected tomaintain records of their continuing professional development (CPD) andmake the records available for review by the Society on request. CPDrecords should contain evidence that practising pharmacists:

(a) continually review the skills and knowledge required for their field(s)of practice, identify those skills or knowledge in need of developmentor improvement and audit their performance as part of the review;

(b) plan appropriate learning activities to address identified learning needsand implement their plans;

(c) evaluate what they have learned and effectively translate their learninginto improved professional practice.

The RPSGB produces guidance on good practice for ensuring professionalcompetence in Medicines, Ethics and Practice: A Guide for Pharmacistswhich is sent to all registered pharmacists on an annual basis. This includesguidance on identifying continuing professional development needs,


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deciding how to meet those needs, recording planning of and participa-tion in CPD and evaluating the outcome of any CPD participation.

All pharmacists, including those eligible to act as Qualified Persons, areencouraged to document any identified training and development needs,how they have planned to meet them and what has actually been done inan attempt to meet them. Pharmacists are advised to retain training recordsand record CPD in an approved format for this purpose.

Continuing Professional Development is becoming increasingly impor-tant in all areas of practice and it is in the interests of all pharma-cists to retain evidence/records of participation. Further informationabout the RPSGB CPD scheme can be found on the RPSGB website at:www.rpsgb.org.

ROYAL SOCIETY OF CHEMISTRY


Continuing Professional Development (CPD) has been defined by the RSCas:

“the responsibility of individuals for the systematic maintenance, improve-ment and broadening of knowledge and skills to ensure continuing com-petence as a professional throughout their career.”

In today’s world, professionals are required to demonstrate that theirknowledge and professional skills are being kept up to date. Advancesin the chemical sciences and the increasing need to use a variety of skillsparticularly when working at the interfaces with different scientific areasrequires members to develop and maintain a range of skills. This will ensurethat they are able to meet the needs of evolving employment requirements.

CPD for RSC members on the Register of Eligible Qualified Personsis important because registrants should be able to demonstrate that theirexpertise is up to date to ensure that the Register has public credibility.The CPD scheme links to the competencies required for registration as anEligible Qualified Person.

Members on the Register of Eligible Qualified Persons is importantbecause registrants should be able to demonstrate that their expertise is upto date to ensure that the Register has public credibility. The CPD schemelinks to the competencies required for registration as an Eligible QualifiedPerson.

Members on the Register of Eligible Qualified Persons are requested tosubmit a CPD return annually. Participation in the scheme is voluntary, butsubmission of an appropriate CPD return will be recognised in the Register.

Further information about the RSC CPD scheme can be found on theRSC website at www.rsc.org/members/cpd.


Import from Third Countries

For medicinal products imported into the EU from third countries (i.e.countries other than the EEA Member States), the provisions of Articles51 and 55, respectively, of Directive 2001/83/EC as amended are requiredto be applied. This includes the full qualitative and quantitative analysis ofat least all the active substances and all the other tests or checks necessaryto ensure the quality of the medicinal products is in accordance with therequirements of the marketing authorisation. It is the Qualified Person ofthe importer who is responsible for ensuring that these requirements aremet.

Mutual Recognition Agreements on Good Manufacturing Practice(GMP) and Manufacturing Authorisation

The European Community has Mutual Recognition Agreements (MRAs)with several third countries with which it has substantial trade. The phar-maceutical or GMP sectors of these MRAs provide benefit to exporters andimporters of medicinal products in the EU trading with these countries.

The basis for an MRA concerning medicinal products is equivalenceof the principles and guidelines of GMP, the inspection systems and, inmost cases, the arrangements for authorising manufacturers between bothparties. An MRA only becomes operational after a mutual agreement ofequivalence. The benefits of an MRA when in operation include:

� authority for an importer to accept a manufacturer’s batch certificationof compliance with GMP, the relevant marketing authorisation and cer-tificate of analysis. The Qualified Person (QP) of the importer in the EUmay certify an imported batch on the basis of such a certificate in placeof full testing within the EU, in accordance with Article 51.2 of Directive2001/83/EC as amended. Importers and exporters who wish to benefitfrom a MRA should use this certificate. The format of the certificate isshown below;

� normal acceptance between competent authorities of inspection reportsand certification of authorisation and GMP compliance of a manufac-turer.

MRAs that include a medicinal products sector have been negotiatedbetween the EC and the following countries:

� Australia� Canada� Japan� New Zealand� Switzerland.


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The MRA between the EC and United States is not in operation. Thetransitional period ended November 2001 but no decision on a formalextension has been taken. The two-way alert systems remain in operation.

The operational status and scope of individual MRAs at any given timemay be checked on the Commission’s website or with the MHRA.

Content of the Fabricator’s/Manufacturer’s Batch Certificate forDrug/Medicinal Products Exported to Countries Under the Scope ofa Mutual Recognition Agreement (MRA)

[Letterhead of exporting manufacturer]

1 Name of product.

Proprietary, brand or trade name in the importing country.

2 Importing country.3 Marketing authorisation number.

The marketing authorisation number of the product in the importing coun-try should be provided.

4 Strength/potency.

Identity (name) and amount per unit dose required for all active ingredi-ents/constituents.

5 Dosage form (pharmaceutical form).6 Package size (contents of container) and type (e.g. vials, bottles,

blisters).7 Lot/batch number.

As related to the product.

8 Date of fabrication/manufacture.

In accordance with national (local) requirements.

9 Expiry date.10 Name and address of fabricator(s)/manufacturer(s) – manufacturing

site(s).

All sites involved in the manufacture including packaging and Quality Con-trol of the batch should be listed with name and address. The name andaddress must correspond to the information provided on the manufactur-ing authorisation/establishment licence.

11 Number of Manufacturing Authorisation/Licence or Certificate ofGMP Compliance of a manufacturer/ fabricator.


The number should be given for each site listed under item 10.

12 Results of analysis.

Should include the authorised specifications, all results obtained and referto the methods used (may refer to a separate certificate of analysis whichmust be dated, signed and attached).

13 Comments/remarks.

Any additional information that can be of value to the importer and/orinspector verifying the compliance of the batch certificate (e.g. specific stor-age or transportation conditions).

14 Certification statement.

This statement should cover the fabrication/manufacturing, includingpackaging and Quality Control. The following text should be used: “Ihereby certify that the above information is authentic and accurate. Thisbatch of product has been fabricated/manufactured, including packagingand Quality Control at the above mentioned site(s) in full compliance withthe GMP requirements of the local Regulatory Authority and with thespecifications in the marketing authorisation of the importing country. Thebatch processing, packaging and analysis records were reviewed and foundto be in compliance with GMP”.

15 Name and position/title of person authorising the batch release.

Including its company/site name and address, if more than one companyis mentioned under item 10.

16 Signature of person authorising the batch release.17 Date of signature.

UK Guidance on Certificates of Analysis

In certain circumstances a Certificate of Analysis from a third party maybe used as part of a system to ensure the quality of materials. For sucha certificate to be considered acceptable the following conditions shouldapply.

(a) The person responsible for Quality Control (QC) in the purchasingcompany must assure himself that the organisation issuing the certifi-cate is competent to do so, whether that organisation is part of thesupplying company or is independent of it (e.g. is a contract analyticalservice).

(b) The Certificate must:(i) Identify the organisation issuing it.


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(ii) Be authorised by a person competent to do so, and state his qual-ifications and position. “Authorisation” may be by signature oracceptable electronic means (please refer to the guidance given forthe similar situation when a Qualified Person (QP) releases a batchof finished products for sale, see paragraph 19 of Annex 11 to theEC Guide to GMP).

(iii) Name the material to which it refers and identify it by a batchnumber.

(iv) State that the material has been tested, by whom and when thiswas done.

(v) State the specification (e.g. EP) and methods against which, andby which, the tests were performed.

(vi) Give the test results obtained, or declare that the results obtainedshowed compliance with the stated specification.

Certificates which merely carry such statements as “a typical analysisis . . .”, or state that the material is of a particular quality with no sup-porting evidence, are not acceptable.

Possession of a Certificate of Analysis does not eliminate the need toconfirm the identity of the material supplied.

Possession of a Certificate of Analysis does not absolve the purchaserfrom ultimate responsibility for the correctness of the material to which itrefers.

The above paragraphs, whilst particularly relevant to the certification ofstarting materials, also apply as appropriate to other materials and prod-ucts.

Note that the Certificate of Analysis described above is not the Manufac-turer’s Batch Certificate used within the context of a Mutual RecognitionAgreement (see Mutual Recognition Agreement section above).

GMP for Starting Materials

(To be read in conjunction with Part II of the EC Guide to GMP.)From 30 October 2005, new Community requirements obliged manu-

facturing authorisation holders to use as starting materials only active sub-stances that have been manufactured in accordance with GMP.

This includes both total and partial manufacture, as well as any repack-aging or re-labelling activities carried out by a distributor or broker. HerbAPIs used as active substances for traditional herbal medicinal products asdefined in Directive 2004/24/EC will also be required to comply with thenew requirements.

The amending legislation gives powers to the competent authorities inMember States to carry out inspections at the premises of manufactur-ers of such materials, the marketing authorisation (MA) holder and any


laboratories employed by the MA holder. These inspections will be con-ducted by the competent authority, may be unannounced and may be car-ried out at the request of an API manufacturer, another Member State,the Commission, or the European Medicines Agency (EMEA). The com-petent authority will be empowered to inspect premises, take samples andexamine documents.

The responsibility for confirming that the active substances in use havebeen manufactured in accordance with GMP rests with the holder of themanufacturing authorisation in the EU. The primary means by which EUregulatory authorities will supervise compliance with the requirement foractive substances to be manufactured in accordance with GMP will bethrough review of audit reports during inspections of manufacturing autho-risation holders.

Audits of API manufacturers should be performed by suitably trainedauditors. During inspections the competence of auditors will be assessedand if not deemed appropriate this will be raised as an issue.

The new Community requirements do not require licensing of API manu-facturers. However, a report will be provided to the manufacturer or MAholder who has undergone the inspection and, where relevant, a certifi-cate of GMP compliance issued. Certificates will be entered on a centralCommunity database, as will be any failures in compliance.

Manufacture and Importation of Unlicensed Medicines forHuman Use

Introduction

UK medicines legislation provides certain exemptions for the supply anduse of unlicensed medicine for human use. Two of the more importantexemptions are outlined here: the manufacture and supply of unlicensedrelevant medicinal products for individual patients (“specials”) and theimportation and supply of unlicensed relevant medicinal products for indi-vidual patients.

A “relevant medicinal product” is one to which the requirements ofDirective 2001/83/EC as amended apply unless subject to an exemption inthat Directive.

Manufacture and supply of unlicensed relevant medicinal products forindividual patients (“specials’’)

The Medicines for Human Use (Marketing Authorisations Etc.) Regula-tions 1994 as amended [SI 1994 No. 3144] require that medicinal productsare licensed before they are marketed in the UK. However some patients


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may have special clinical needs that cannot be met by licensed medicinalproducts. So that these special needs may be met, the law allows manu-facture and supply of unlicensed medicinal products (commonly known as“specials”), subject to certain conditions.

The conditions, laid down in Schedule 1 of the Regulations, are thatthere is a bona fide unsolicited order, the product is formulated in accor-dance with the requirement of a doctor or dentist registered in the UKand the product is for use by one of their individual patients (on the basisof “special need“) on the practitioner’s direct personal responsibility. If a“special” is manufactured in the UK, the manufacturer must hold a manu-facturer’s (specials) licence issued by the MHRA. A “special” may notbe advertised and may not be supplied if an equivalent licensed productis available which could meet the patient’s needs. Essential records mustbe kept and serious adverse drug reactions reported to the MHRA. TheMHRA Guidance Note 14 The supply of unlicensed relevant medicinalproducts for individual patients provides guidance to manufacturers aboutthe conditions under which they may manufacture and supply “specials”and their legal obligations.

Importation and supply of unlicensed relevant medicinal products forindividual patients

An unlicensed relevant medicinal product may only be importedin accordance with The Medicines for Human Use (Manufacturing,Wholesale Dealing and Miscellaneous Amendments) Regulations 2005[SI 2005/2789]. An importer must hold the appropriate wholesale dealer’sor manufacturer’s (import) licence (for further information see the MHRAGuidance Notes 5 and 6: Notes for applicants and holders of a manufac-turer’s/wholesale dealer’s licence) and must comply with the conditions oftheir licence. Wholesale dealers and importers from third countries licenceconditions include the requirement that they must notify the MHRA oneach occasion that they intend to import such a product. Importation mayproceed unless the importer has been informed by the MHRA within 28days that it objects to importation. The MHRA may object and preventimportation because it has concerns about the safety or quality of the prod-uct or because there is an equivalent licensed medicinal product availableand it is not satisfied that there is a “special need” for the supply to anindividual patient.

An imported unlicensed relevant medicinal product may only be sup-plied in accordance with Schedule 1 to The Medicines for Human Use(Marketing Authorisations Etc.) Regulations 1994 as amended [SI 1994No. 3144]. Schedule 1 exempts, under defined conditions (discussed in theprevious section on “specials”) such a product when it is supplied to meet


the “special need” of an individual patient. The MHRA Guidance Note 14provides guidance to importers about the conditions under which they mayimport and supply unlicensed relevant medicinal products and their legalobligations.

The manufacturer or assembler of “specials” must also demonstratecompliance with the European Commission’s Notes for guidance on min-imising the risk of transmitting animal spongiform encephalopathy agentsvia medicinal products and future updates, in accordance with The Unli-censed Medicinal Products for Human Use (Transmissible SpongiformEncephalopathies) (Safety) Regulations 2003 [SI 2003/1680]. (See theMHRA’s interim guidance: Minimising the risk of Transmission of Trans-missible Spongiform Encephalopathies via Unlicensed Medicinal Productsfor Human Use, available from the MHRA’s website www.mhra.gov.uk.)

Contact

For further information about notifications of intention to import, pleasecontact:

The Unlicensed Imports Section, 17th floor, Market Towers, 1 Nine ElmsLane, London SW8 5NQ, UK.

Telephone: +44 (0)20 7084 2574Fax: +44 (0)20 7084 2676E-mail: [email protected]

SECTION

III

LEGISLATION ONMANUFACTURE

CHAPTER

4

EU Legislation on Manufacture

Contents

Directive 2001/83/EC, as Amended,Title IV, Manufacture andImportation 300

Directive 2001/83/EC of theEuropean Parliament and of theCouncil of 6 November 2001 onthe Community code relating tomedicinal products for human useas amended by Directive2004/27/EC 300

Title IV: Manufacture andImportation 300

Article 40 300Article 41 300Article 42 301Article 43 301Article 44 301Article 45 302Article 46 302Article 46a 302Article 47 303Article 48 303Article 49 303Article 50 305Article 51 305Article 52 306

Directive 2003/94/EC, Laying Downthe Principles and Guidelines ofGood Manufacturing Practice forHuman Medicines 306

Directive 2003/94/EC, laying downthe principles and guidelines ofgood manufacturing practice inrespect of medicinal products forhuman use and investigationalmedicinal products for humanuse 306

Article 1 307Article 2 307Article 3 307Article 4 308Article 5 308Article 6 309Article 7 309Article 8 310Article 9 310Article 10 311Article 11 311Article 12 312Article 13 313Article 14 313Article 15 314Article 16 314Article 17 314Article 18 314Article 19 314

299

300 III LEGISLATION ON MANUFACTURE

DIRECTIVE 2001/83/EC, AS AMENDED, TITLE IV,MANUFACTURE AND IMPORTATION

Directive 2001/83/EC of the European Parliament and of the Councilof 6 November 2001 on the Community code relating to medicinalproducts for human use as amended by Directive 2004/27/EC

Title IV: Manufacture and Importation

Editor’snote

Title IV of this directive is reproduced below. Reference should be made tothe full Directive for the preamble, definitions and the general and finalprovisions.

Article 40

1 Member States shall take all appropriate measures to ensure that the manu-facture of the medicinal products within their territory is subject to theholding of an authorization. This manufacturing authorization shall berequired notwithstanding that the medicinal products manufactured areintended for export.

2 The authorization referred to in paragraph 1 shall be required for bothtotal and partial manufacture, and for the various processes of dividingup, packaging or presentation. However, such authorization shall not berequired for preparation, dividing up, changes in packaging or presen-tation where these processes are carried out, solely for retail supply, bypharmacists in dispensing pharmacies or by persons legally authorized inthe Member States to carry out such processes.

3 Authorization referred to in paragraph 1 shall also be required for importscoming from third countries into a Member State; this Title and Article118 shall have corresponding application to such imports as they have tomanufacture.

4 The Member States shall forward to the Agency a copy of the authorisationreferred to in paragraph 1. The Agency shall enter that information on theCommunity database referred to in Article 111(6).

Article 41

In order to obtain the manufacturing authorization, the applicant shallmeet at least the following requirements:


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(a) specify the medicinal products and pharmaceutical forms which are tobe manufactured or imported and also the place where they are to bemanufactured and/or controlled;

(b) have at his disposal, for the manufacture or import of the above, suit-able and sufficient premises, technical equipment and control facili-ties complying with the legal requirements which the Member Stateconcerned lays down as regards both manufacture and control and thestorage of medicinal products, in accordance with Article 20;

(c) have at his disposal the services of at least one qualified person withinthe meaning of Article 48. The applicant shall provide particulars insupport of the above in his application.

Article 42

1 The competent authority of the Member State shall issue the manufacturingauthorization only after having made sure of the accuracy of the particularssupplied pursuant to Article 41, by means of an inquiry carried out by itsagents.

2 In order to ensure that the requirements referred to in Article 41 are com-plied with, authorization may be made conditional on the carrying out ofcertain obligations imposed either when authorization is granted or at alater date.

3 The authorization shall apply only to the premises specified in the applica-tion and to the medicinal products and pharmaceutical forms specified inthat same application.

Article 43

The Member States shall take all appropriate measures to ensure that thetime taken for the procedure for granting the manufacturing authorizationdoes not exceed 90 days from the day on which the competent authorityreceives the application.

Article 44

If the holder of the manufacturing authorization requests a change in anyof the particulars referred to in points (a) and (b) of the first paragraph ofArticle 41, the time taken for the procedure relating to this request shall notexceed 30 days. In exceptional cases this period of time may be extendedto 90 days.


Article 45

The competent authority of the Member State may require from the appli-cant further information concerning the particulars supplied pursuant toArticle 41 and concerning the qualified person referred to in Article 48;where the competent authority concerned exercises this right, applicationof the time-limits referred to in Article 43 and 44 shall be suspended untilthe additional data required have been supplied.

Article 46

The holder of a manufacturing authorization shall at least be obliged:

(a) to have at his disposal the services of staff who comply with the legalrequirements existing in the Member State concerned both as regardsmanufacture and controls;

(b) to dispose of the authorized medicinal products only in accordancewith the legislation of the Member States concerned;

(c) to give prior notice to the competent authority of any changes he maywish to make to any of the particulars supplied pursuant to Article 41;the competent authority shall, in any event, be immediately informed ifthe qualified person referred to in Article 48 is replaced unexpectedly;

(d) to allow the agents of the competent authority of the Member Stateconcerned access to his premises at any time;

(e) to enable the qualified person referred to in Article 48 to carry out hisduties, for example by placing at his disposal all the necessary facilities;

(f) to comply with the principles and guidelines of good manufacturingpractice for medicinal products and to use as starting materials onlyactive substances, which have been manufactured in accordance withthe detailed guidelines on good manufacturing practice for startingmaterials. This point shall also be applicable to certain excipients, thelist of which as well as the specific conditions of application shall beestablished by a Directive adopted by the Commission in accordancewith the procedure referred to in Article 121(2).

Article 46a

1 For the purposes of this Directive, manufacture of active substances usedas starting materials shall include both total and partial manufacture orimport of an active substance used as a starting material as defined inPart I, point 3.2.1.1 (b) Annex I, and the various processes of dividingup, packaging or presentation prior to its incorporation into a medicinalproduct, including repackaging or relabelling, such as are carried out by adistributor of starting materials.


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2 Any amendments necessary to adapt paragraph 1 to new scientific and tech-nical developments shall be laid down in accordance with the procedurereferred to in Article 121(2).

Article 47

The principles and guidelines of good manufacturing practices for medi-cinal products referred to in Article 46(f) shall be adopted in the form ofa directive, in accordance with the procedure referred to in Article 121(2).Detailed guidelines in line with those principles will be published by theCommission and revised necessary to take account of technical and scien-tific progress. The principles of good manufacturing practice for active sub-stances used as starting materials referred to in point (f) of Article 46 shallbe adopted in the form of detailed guidelines. The Commission shall alsopublish guidelines on the form and content of the authorisation referredto in Article 40(1), on the reports referred to in Article 111(3) and on theform and content of the certificate of good manufacturing practice referredto in Article 111(5).

Article 48

1 Member States shall take all appropriate measures to ensure that the holderof the manufacturing authorization has permanently and continuously athis disposal the services of at least one qualified person, in accordancewith the conditions laid down in Article 49, responsible in particular forcarrying out the duties specified in Article 51.

2 If he personally fulfils the conditions laid down in Article 49, the holderof the authorization may himself assume the responsibility referred to inparagraph 1.

Article 49

1 Member States shall ensure that the qualified person referred to in Article48 fulfils the conditions of qualification set out in paragraphs 2 and 3.

2 A qualified person shall be in possession of a diploma, certificate or otherevidence of formal qualifications awarded on completion of a universitycourse of study, or a course recognized as equivalent by the Member Stateconcerned, extending over a period of at least four years of theoreticaland practical study in one of the following scientific disciplines: pharmacy,medicine, veterinary medicine, chemistry, pharmaceutical chemistry andtechnology, biology.

However, the minimum duration of the university course may be threeand a half years where the course is followed by a period of theoreticaland practical training of a minimum duration of one year and including


a training period of at least six months in a pharmacy open to the public,corroborated by an examination at university level.

Where two university courses or two courses recognized by the State asequivalent co-exist in a Member State and where one of these extends overfour years and the other over three years, the three-year course leading toa diploma, certificate or other evidence of formal qualifications awardedon completion of a university course or its recognized equivalent shallbe considered to fulfil the condition of duration referred to in the secondsubparagraph in so far as the diplomas, certificates or other evidence of for-mal qualifications awarded on completion of both courses are recognizedas equivalent by the State in question.

The course shall include theoretical and practical study bearing upon atleast the following basic subjects:

� Experimental physics� General and inorganic chemistry� Organic chemistry� Analytical chemistry� Pharmaceutical chemistry, including analysis of medicinal products� General and applied biochemistry (medical)� Physiology� Microbiology� Pharmacology� Pharmaceutical technology� Toxicology� Pharmacognosy (study of the composition and effects of the natural

active substances of plant and animal origin).

Studies in these subjects should be so balanced as to enable the personconcerned to fulfil the obligations specified in Article 51.

In so far as certain diplomas, certificates or other evidence of formalqualifications mentioned in the first subparagraph do not fulfil the crite-ria laid down in this paragraph, the competent authority of the MemberState shall ensure that the person concerned provides evidence of adequateknowledge of the subjects involved.

3 The qualified person shall have acquired practical experience over at leasttwo years, in one or more undertakings which are authorized to manufac-ture medicinal products, in the activities of qualitative analysis of medicinalproducts, of quantitative analysis of active substances and of the testingand checking necessary to ensure the quality of medicinal products.

The duration of practical experience may be reduced by one year wherea university course lasts for at least five years and by a year and a halfwhere the course lasts for at least six years.


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Article 50

1 A person engaging in the activities of the person referred to in Article 48from the time of the application of Directive 75/319/EEC, in a MemberState without complying with the provisions of Article 49 shall be eligibleto continue to engage in those activities within the Community.

2 The holder of a diploma, certificate or other evidence of formal qualifica-tions awarded on completion of a university course or a course recognizedas equivalent by the Member State concerned in a scientific discipline allow-ing him to engage in the activities of the person referred to in Article 48 inaccordance with the laws of that State may – if he began his course prior to21 May 1975 – be considered as qualified to carry out in that State theduties of the person referred to in Article 48 provided that he has previ-ously engaged in the following activities for at least two years before 21May1985 following notification of this directive in one or more undertakingsauthorized to manufacture: production supervision and/or qualitative andquantitative analysis of active substances, and the necessary testing andchecking under the direct authority of the person referred to in Article 48to ensure the quality of the medicinal products.

If the person concerned has acquired the practical experience referredto in the first subparagraph before 21 May 1965, a further one year’spractical experience in accordance with the conditions referred to in thefirst subparagraph will be required to be completed immediately before heengages in such activities.

Article 51

1 Member States shall take all appropriate measures to ensure that the qual-ified person referred to in Article 48, without prejudice to his relationshipwith the holder of the manufacturing authorization, is responsible, in thecontext of the procedures referred to in Article 52, for securing:

(a) in the case of medicinal products manufactured within the MemberStates concerned, that each batch of medicinal products has been man-ufactured and checked in compliance with the laws in force in thatMember State and in accordance with the requirements of the market-ing authorisation;

(b) in the case of medicinal products coming from third countries, irrespec-tive of whether the product has been manufactured in the Community,that each production batch has undergone in a Member State a fullqualitative analysis, a quantitative analysis of at least all the activesubstances and all the other tests or checks necessary to ensure thequality of medicinal products in accordance with the requirements ofthe marketing authorisation.


The batches of medicinal products which have undergone such controls ina Member State shall be exempt from the controls if they are marketed inanother Member State, accompanied by the control reports signed by thequalified person.

2 In the case of medicinal products imported from a third country, whereappropriate arrangements have been made by the Community with theexporting country to ensure that the manufacturer of the medicinal productapplies standards of good manufacturing practice at least equivalent tothose laid down by the Community, and to ensure that the controls referredto under point (b) of the first subparagraph of paragraph 1 have beencarried out in the exporting country, the qualified person may be relievedof responsibility for carrying out those controls.

3 In all cases and particularly where the medicinal products are released forsale, the qualified person must certify in a register or equivalent documentprovided for that purpose, that each production batch satisfies the provi-sions of this Article; the said register or equivalent document must be keptup to date as operations are carried out and must remain at the disposal ofthe agents of the competent authority for the period specified in the provi-sions of the Member State concerned and in any event for at least five years.

Article 52

Member States shall ensure that the duties of qualified persons referredto in Article 48 are fulfilled, either by means of appropriate administra-tive measures or by making such persons subject to a professional codeof conduct. Member States may provide for the temporary suspension ofsuch a person upon the commencement of administrative or disciplinaryprocedures against him for failure to fulfil his obligations.

DIRECTIVE 2003/94/EC, LAYING DOWN THE PRINCIPLES ANDGUIDELINES OF GOOD MANUFACTURING PRACTICE FORHUMAN MEDICINES

Directive 2003/94/EC, laying down the principles and guidelines ofgood manufacturing practice in respect of medicinal products forhuman use and investigational medicinal products for human use

Editor’snote

The Articles of this Directive are reproduced below. Reference should bemade to the full Directive for the preambles.


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Article 1

SCOPE

This Directive lays down the principles and guidelines of good manufactur-ing practice in respect of medicinal products for human use whose manu-facture requires the authorisation referred to in Article 40 of Directive2001/83/EC and in respect of investigational medicinal products for humanuse whose manufacture requires the authorisation referred to in Article 13of Directive 2001/20/EC.

Article 2

DEFINITIONS

For the purposes of this Directive, the following definitions shall apply:

1 “medicinal product” means any product as defined in Article 1(2) of Direc-tive 2001/83/EC;

2 “investigational medicinal product” means any product as defined in Arti-cle 2(d) of Directive 2001/20/EC;

3 “manufacturer” means any person engaged in activities for which theauthorisation referred to in Article 40(1) and (3) of Directive 2001/83/ECor the authorisation referred to in Article 13(1) of Directive 2001/20/ECis required;

4 “qualified person” means the person referred to in Article 48 of Directive2001/83/EC or in Article 13(2) of Directive 2001/20/EC;

5 “pharmaceutical quality assurance” means the total sum of the organisedarrangements made with the object of ensuring that medicinal productsor investigational medicinal products are of the quality required for theirintended use;

6 “good manufacturing practice” means the part of quality assurance whichensures that products are consistently produced and controlled in accor-dance with the quality standards appropriate to their intended use;

7 “blinding” means the deliberate disguising of the identity of an investiga-tional medicinal product in accordance with the instructions of the sponsor;

8 “unblinding” means the disclosure of the identity of a blinded product.

Article 3

INSPECTIONS

1 By means of the repeated inspections referred to in Article 111(1) of Direc-tive 2001/83/EC and by means of the inspections referred to in Article 15(1)


of Directive 2001/20/EC, the Member States shall ensure that manufactur-ers respect the principles and guidelines of good manufacturing practicelaid down by this Directive. Member States shall also take into account thecompilation, published by the Commission, of Community procedures oninspections and exchange of information.

2 For the interpretation of the principles and guidelines of good manufactur-ing practice, the manufacturers and the competent authorities shall takeinto account the detailed guidelines referred to in the second paragraphof Article 47 of Directive 2001/83/EC, published by the Commission inthe “Guide to good manufacturing practice for medicinal products and forinvestigational medicinal products”.

Article 4

CONFORMITY WITH GOOD MANUFACTURING PRACTICE

1 The manufacturer shall ensure that manufacturing operations are carriedout in accordance with good manufacturing practice and with the manufac-turing authorisation. This provision shall also apply to medicinal productsintended only for export.

2 For medicinal products and investigational medicinal products importedfrom third countries, the importer shall ensure that the products have beenmanufactured in accordance with standards which are at least equivalent tothe good manufacturing practice standards laid down by the Community.

In addition, an importer of medicinal products shall ensure that suchproducts have been manufactured by manufacturers duly authorised todo so. An importer of investigational medicinal products shall ensure thatsuch products have been manufactured by a manufacturer notified to thecompetent authorities and accepted by them for that purpose.

Article 5

COMPLIANCE WITH MARKETING AUTHORISATION

1 The manufacturer shall ensure that all manufacturing operations for medi-cinal products subject to a marketing authorisation are carried out in ac-cordance with the information provided in the application for market-ing authorisation as accepted by the competent authorities.

In the case of investigational medicinal products, the manufacturer shallensure that all manufacturing operations are carried out in accordancewith the information provided by the sponsor pursuant to Article 9(2) ofDirective 2001/20/EC as accepted by the competent authorities.


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2 The manufacturer shall regularly review his manufacturing methods inthe light of scientific and technical progress and the development of theinvestigational medicinal product.

If a variation to the marketing authorisation dossier or an amendmentto the request referred to in Article 9(2) of Directive 2001/20/EC is neces-sary, the application for modification shall be submitted to the competentauthorities.

Article 6

QUALITY ASSURANCE SYSTEM

The manufacturer shall establish and implement an effective pharmaceu-tical quality assurance system, involving the active participation of themanagement and personnel of the different departments.

Article 7

PERSONNEL

1 At each manufacturing site, the manufacturer shall have a sufficient num-ber of competent and appropriately qualified personnel at his disposal toachieve the pharmaceutical quality assurance objective.

2 The duties of the managerial and supervisory staff, including the qualifiedpersons, responsible for implementing and operating good manufacturingpractice, shall be defined in job descriptions. Their hierarchical relation-ships shall be defined in an organisation chart. Organisation charts andjob descriptions shall be approved in accordance with the manufacturer’sinternal procedures.

3 The staff referred to in paragraph 2 shall be given sufficient authority todischarge their responsibility correctly.

4 The personnel shall receive initial and ongoing training, the effectivenessof which shall be verified, covering in particular the theory and applica-tion of the concept of quality assurance and good manufacturing practice,and, where appropriate, the particular requirements for the manufactureof investigational medicinal products.

5 Hygiene programmes adapted to the activities to be carried out shallbe established and observed. These programmes shall, in particular,include procedures relating to health, hygiene practice and clothing ofpersonnel.


Article 8

PREMISES AND EQUIPMENT

1 Premises and manufacturing equipment shall be located, designed, con-structed, adapted and maintained to suit the intended operations.

2 Premises and manufacturing equipment shall be laid out, designed andoperated in such a way as to minimise the risk of error and to permiteffective cleaning and maintenance in order to avoid contamination, cross-contamination and, in general, any adverse effect on the quality of theproduct.

3 Premises and equipment to be used for manufacturing operations, whichare critical to the quality of the products, shall be subjected to appropriatequalification and validation.

Article 9

DOCUMENTATION

1 The manufacturer shall establish and maintain a documentation systembased upon specifications, manufacturing formulae and processing andpackaging instructions, procedures and records covering the various manu-facturing operations performed. Documents shall be clear, free from errorand kept up to date. Pre-established procedures for general manufacturingoperations and conditions shall be kept available, together with specificdocuments for the manufacture of each batch. That set of documents shallenable the history of the manufacture of each batch and the changes intro-duced during the development of an investigational medicinal product tobe traced.

For a medicinal product, the batch documentation shall be retained forat least one year after the expiry date of the batches to which it relatesor at least five years after the certification referred to in Article 51(3) ofDirective 2001/83/EC, whichever is the longer period.

For an investigational medicinal product, the batch documentation shallbe retained for at least five years after the completion or formal discontin-uation of the last clinical trial in which the batch was used. The sponsor ormarketing authorisation holder, if different, shall be responsible for ensur-ing that records are retained as required for marketing authorisation inaccordance with the Annex I to Directive 2001/83/EC, if required for asubsequent marketing authorisation.

2 When electronic, photographic or other data processing systems are usedinstead of written documents, the manufacturer shall first validate the sys-tems by showing that the data will be appropriately stored during the antic-ipated period of storage. Data stored by those systems shall be made readilyavailable in legible form and shall be provided to the competent authorities


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at their request. The electronically stored data shall be protected, by meth-ods such as duplication or back-up and transfer on to another storagesystem, against loss or damage of data, and audit trails shall be maintained.

Article 10

PRODUCTION

1 The different production operations shall be carried out in accordance withpre-established instructions and procedures and in accordance with goodmanufacturing practice. Adequate and sufficient resources shall be madeavailable for the in-process controls. All process deviations and productdefects shall be documented and thoroughly investigated.

2 Appropriate technical or organisational measures shall be taken to avoidcross-contamination and mix-ups. In the case of investigational medicinalproducts, particular attention shall be paid to the handling of productsduring and after any blinding operation.

3 For medicinal products, any new manufacture or important modification ofa manufacturing process of a medicinal product shall be validated. Criticalphases of manufacturing processes shall be regularly re-validated.

4 For investigational medicinal products, the manufacturing process shall bevalidated in its entirety in so far as is appropriate, taking into account thestage of product development. At least the critical process steps, such assterilisation, shall be validated. All steps in the design and development ofthe manufacturing process shall be fully documented.

Article 11

QUALITY CONTROL

1 The manufacturer shall establish and maintain a quality control systemplaced under the authority of a person who has the requisite qualificationsand is independent of production. That person shall have at his disposal,or shall have access to, one or more quality control laboratories appro-priately staffed and equipped to carry out the necessary examination andtesting of the starting materials and packaging materials and the testing ofintermediate and finished products.

2 For medicinal products, including those imported from third countries,contract laboratories may be used if authorised in accordance with Article12 of this Directive and point (b) of Article 20 of Directive 2001/83/EC.

For investigational medicinal products, the sponsor shall ensure thatthe contract laboratory complies with the content of the request referredto in Article 9(2) of Directive 2001/20/EC, as accepted by the competent


authority. When the products are imported from third countries, analyticalcontrol shall not be mandatory.

3 During the final control of the finished product before its release for saleor distribution or for use in clinical trials, the quality control system shalltake into account, in addition to analytical results, essential informationsuch as the production conditions, the results of in-process controls, theexamination of the manufacturing documents and the conformity of theproduct to its specifications, including the final finished pack.

4 Samples of each batch of finished medicinal product shall be retained forat least one year after the expiry date. For an investigational medicinalproduct, sufficient samples of each batch of bulk formulated product andof key packaging components used for each finished product batch shall beretained for at least two years after completion or formal discontinuationof the last clinical trial in which the batch was used, whichever period isthe longer.

Unless a longer period is required under the law of the Member Stateof manufacture, samples of starting materials, other than solvents, gasesor water, used in the manufacturing process shall be retained for at leasttwo years after the release of product. That period may be shortened if theperiod of stability of the material, as indicated in the relevant specification,is shorter. All those samples shall be maintained at the disposal of the com-petent authorities. Other conditions may be defined, by agreement with thecompetent authority, for the sampling and retaining of starting materialsand certain products manufactured individually or in small quantities, orwhen their storage could raise special problems.

Article 12

WORK CONTRACTED OUT

1 Any manufacturing operation or operation linked thereto which is carriedout under contract shall be the subject of a written contract.

2 The contract shall clearly define the responsibilities of each party and shalldefine, in particular, the observance of good manufacturing practice to befollowed by the contract acceptor and the manner in which the qualifiedperson responsible for certifying each batch is to discharge his responsibil-ities.

3 The contract-acceptor shall not subcontract any of the work entrusted tohim under the contract without written authorisation from the contract-giver.

4 The contract-acceptor shall comply with the principles and guidelines ofgood manufacturing practice and shall submit to inspections carried out by


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the competent authorities pursuant to Article 111 of Directive 2001/83/ECand Article 15 of Directive 2001/20/EC.

Article 13

COMPLAINTS, PRODUCT RECALL AND EMERGENCY UNBLINDING

1 In the case of medicinal products, the manufacturer shall implement asystem for recording and reviewing complaints together with an effectivesystem for recalling, promptly and at any time, medicinal products in thedistribution network. Any complaint concerning a defect shall be recordedand investigated by the manufacturer. The manufacturer shall inform thecompetent authority of any defect that could result in a recall or abnormalrestriction on supply and, in so far as is possible, indicate the countries ofdestination. Any recall shall be made in accordance with the requirementsreferred to in Article 123 of Directive 2001/83/EC.

2 In the case of investigational medicinal products, the manufacturer shall,in cooperation with the sponsor, implement a system for recording andreviewing complaints together with an effective system for recallingpromptly and at any time investigational medicinal products which havealready entered the distribution network. The manufacturer shall recordand investigate any complaint concerning a defect and shall inform thecompetent authority of any defect that could result in a recall or abnormalrestriction on supply.

In the case of investigational medicinal products, all trial sites shall beidentified and, in so far as is possible, the countries of destination shall beindicated.

In the case of an investigational medicinal product for which a mar-keting authorisation has been issued, the manufacturer of the investiga-tional medicinal product shall, in cooperation with the sponsor, inform themarketing authorisation holder of any defect that could be related to theauthorised medicinal product.

3 The sponsor shall implement a procedure for the rapid unblinding ofblinded products, where this is necessary for a prompt recall as referred toin paragraph 2. The sponsor shall ensure that the procedure discloses theidentity of the blinded product only in so far as is necessary.

Article 14

SELF-INSPECTION

The manufacturer shall conduct repeated self-inspections as part of thequality assurance system in order to monitor the implementation andrespect of good manufacturing practice and to propose any necessary


corrective measures. Records shall be maintained of such self-inspectionsand any corrective action subsequently taken.

Article 15

LABELLING

In the case of an investigational medicinal product, labelling shall be such asto ensure protection of the subject and traceability, to enable identificationof the product and trial, and to facilitate proper use of the investigationalmedicinal product.

Article 16

REPEAL OF DIRECTIVE 91/356/EEC

Directive 91/356/EEC is repealed. References to the repealed Directive shallbe construed as references to this Directive.

Article 17

TRANSPOSITION

1 Member States shall bring into force the laws, regulations and administra-tive provisions necessary to comply with this Directive by 30 April 2004 atthe latest. They shall forthwith communicate to the Commission the textof the provisions and correlation table between those provisions and theprovisions of this Directive.

When Member States adopt those provisions, they shall contain a refer-ence to this Directive or be accompanied by such a reference on the occasionof their official publication. The Member States shall determine how suchreference is to be made.

2 Member States shall communicate to the Commission the text of the mainprovisions of national law which they adopt in the field covered by thisDirective.

Article 18

ENTRY INTO FORCE

This Directive shall enter into force on the 20th day following that of itspublication in the Official Journal of the European Union.

Article 19

ADDRESSEES

This Directive is addressed to the Member States.

CHAPTER

5

UK Legislation on Manufacture

Contents

The Medicines for Human Use(Manufacturing, Wholesale Dealingand Miscellaneous Amendments)Regulations 2005 (SI 2005No. 2789) 316

Interpretation 316Requirement that manufacturer’s

licence holders comply with certainobligations in relation to themanufacture and assembly ofrelevant medicinal products 317

Requirement that manufacturer’slicence holders comply with certainobligations in relation to the importfrom a third country of relevantmedicinal products 319

Requirements as to qualifiedpersons 320

Offence relating to the sale and supplyof starting materials for use in themanufacture of relevant medicinalproducts 322

Additional standard provisions formanufacturer’s licences which relateto vaccines, toxins and sera 322

Schedule 1 of the Regulations 323Standard provisions which may be

incorporated in a manufacturer’slicence relating to the manufactureand assembly of relevant medicinalproducts 323

Schedule 2 of the Regulations 326

Standard provisions which may beincorporated in a manufacturer’slicence relating to the import ofrelevant medicinal products from athird country 326

Schedule 3 of the Regulations 329Standard provisions which may be

incorporated in a manufacturer’slicence which relates tovaccines 329

Standard provisions which may beincorporated in a manufacturer’slicence which relates to smallpoxvaccines 330

Standard provisions which may beincorporated in a manufacturer’slicence which relates to BCGvaccines 331

Standard provisions which may beincorporated in a manufacturer’slicence which relates to toxins 333

Standard provisions which may beincorporated in a manufacturer’slicence which relates to sera 333

Prescribed Conditions forManufacturer’s Undertakings forImported Products (SI 1977No. 1038) 335

Schedule 335Prescribed conditions for

manufacturer’s undertakings 335

315


The Medicines for Human Use (Manufacturing, Wholesale Dealingand Miscellaneous Amendments) Regulations 2005 (SI 2005No. 2789)

Editor’snote

These extracts from the Regulations and Standard Provisions of TheMedicines for Human Use (Manufacturing, Wholesale Dealing andMiscellaneous Amendments) Regulations 2005 No. 2789 are presented forthe reader’s convenience. Reproduction is with the permission of HMSO andthe Queen’s Printer for Scotland. For any definitive information referencemust be made to the original Regulations.

The numbering and content within this section corresponds with theregulations set out in the published Statutory Instrument 2005 No. 2789.

Interpretation

1 (1) These Regulations may be cited as the Medicines for Human Use(Manufacturing, Wholesale Dealing and Miscellaneous Amendments)Regulations 2005.

(2) In these Regulations:

“the Act” means the Medicines Act 1968;“the 1994 Regulations” means the Medicines for Human Use (Mar-

keting Authorisations Etc.) Regulations 1994;“the Applications Regulations” means the Medicines (Applications

for Manufacturer’s and Wholesale Dealer’s Licences) Regulations1971;

“the Standard Provisions Regulations” means the Medicines (StandardProvisions for Licences and Certificates) Regulations 1971;

“Commission Directive 2003/94/EC” means Commission Directive2003/94/EC laying down the principles and guidelines of goodmanufacturing practice in respect of medicinal products forhuman use and for investigational medicinal products for humanuse;

“the Directive” means Directive 2001/83/EC, of the European Parlia-ment and of the Council on the Community code relating to medi-cinal products for human use, as amended by:

(a) Directive 2002/98/EC of the European Parliament and of theCouncil of 27 January 2003 setting standards of quality andsafety for the collection, testing, processing, storage and distri-bution of human blood and blood components,


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(b) Commission Directive 2003/63/EC amending Directive2001/83/EC on the Community code relating to medicinalproducts for human use,

(c) Directive 2004/24/EC of the European Parliament and of theCouncil amending, as regards traditional herbal medicinalproducts, Directive 2001/83/EC on the Community code relat-ing to medicinal products for human use and

(d) Directive 2004/27/EC of the European Parliament and of theCouncil amending Directive 2001/83/EC on the Communitycode relating to medicinal products for human use;

“EEA State” means a member State, Norway, Iceland or Liecht-enstein;

“the guidelines on good distribution practice” means theGuidelines on Good Distribution Practice of MedicinalProducts for Human Use (94/C63/03) published by theEuropean Commission pursuant to Article 84 of theDirective;

“the principles and guidelines of good manufacturing practice”means the principles and guidelines of good manufacturingpractice set out in Commission Directive 2003/ 94/EC.

Requirement that manufacturer’s licence holders comply with certainobligations in relation to the manufacture and assembly of relevantmedicinal products

2 (1) In relation to the manufacture and assembly of relevant medicinal prod-ucts, a manufacturer’s licence holder shall:(a) comply with the principles and guidelines of good manufacturing

practice;(b) comply with the requirements of paragraph (3); and(c) subject to paragraph (2), use active substances as starting materi-

als only where those active substances have been manufactured orassembled in accordance with the principles and guidelines of goodmanufacturing practice applicable to starting materials;

(2) A manufacturer’s licence holder shall not be required to comply withthe requirement of paragraph (1)(c) in relation to the manufacture orassembly of relevant medicinal products pursuant to his manufacturer’slicence, insofar as such activity is limited to the manufacture or assem-bly of exempt relevant medicinal products.

(3) The requirements of this paragraph are that the manufacturer’s licenceholder shall:


(a) maintain such staff, premises, equipment and facilities as are nec-essary for such stages of the manufacture and assembly of relevantmedicinal products as are undertaken by him in accordance withthe requirements of:(i) his licence, and(ii) the marketing authorizations of the relevant medicinal products

in question;(b) maintain such staff, premises, equipment and facilities for the han-

dling, control, storage and distribution of the relevant medicinalproducts which he handles, stores and distributes under his licence,as are necessary to maintain the quality of those medicinal products;

(c) ensure that any arrangements he makes with any person for thecontrol, storage and distribution of the relevant medicinal productsare adequate to maintain the quality of those products;

(d) not carry out any manufacture or assembly of relevant medicinalproducts other than:(i) the manufacture or assembly of those classes of relevant medic-

inal product specified in his licence, and(ii) at the premises specified in his licence;

(e) not use any premises for the handling, control, storage or distribu-tion of relevant medicinal products other than those specified in hislicence as approved by the licensing authority for that purpose, orapproved by the licensing authority for that purpose from time totime;

(f) inform the licensing authority before making any material alter-ation to the premises or facilities used under his licence, or in theoperations for which they are used;

(g) inform the licensing authority of any change that he proposes tomake to any personnel named in his licence as responsible for qual-ity control of the medicinal products being manufactured or assem-bled by him, including the person named as the qualified person forthe purposes of regulation 4;

(h) for the purpose of enabling the licensing authority to ascertainwhether there are any grounds:(i) for suspending, revoking or varying any licence granted under

Part II of the Act; or(ii) suspending or terminating any licence in accordance with the

provisions of Part II of the Act, permit, and provide all neces-sary facilities to enable, any person duly authorised in writingby the licensing authority, on production if required of his cre-dentials, to carry out such inspection or to take such samplesor copies, in relation to things belonging to, or any businesscarried on by, the holder of the licence, as such person wouldhave the right to carry out or take under the Act for the purpose


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of verifying any statement contained in an application for alicence;

(i) ensure that any blood or blood component imported into the UnitedKingdom and used by him as a starting material or raw material inthe manufacture of a relevant medicinal product shall meet equiva-lent standards of quality and safety to those laid down in Commis-sion Directive 2004/33/EC, implementing Directive 2002/98/ECof the European Parliament and of the Council as regards cer-tain technical requirements for blood and blood components;and

(j) shall, where he distributes by way of wholesale dealing, any rele-vant medicinal product manufactured or assembled pursuant to hislicence, comply with the requirements of regulations 8(1)(a) and (b)and (2), and 9 (2) and (3), as if he was the holder of a wholesaledealer’s licence.

Requirement that manufacturer’s licence holders comply with certainobligations in relation to the import from a third country of relevantmedicinal products

3 In relation to the import from a third country of any relevant medicinalproduct, a manufacturer’s licence holder shall:

(a) comply with the principles and guidelines of good manufacturing prac-tice insofar as they are relevant to the import of relevant medicinalproducts;

(b) comply with the guidelines on good distribution practice;(c) ensure that any relevant medicinal products (other than exempt rele-

vant medicinal products) imported by him from a third country useactive substances as starting materials only where those active sub-stances have been manufactured in accordance with the principlesand guidelines of good manufacturing practice applicable to startingmaterials;

(d) maintain such staff, premises, equipment and facilities for the han-dling, control, storage and distribution of the relevant medicinal prod-ucts which he handles, stores and distributes under his licence, as arenecessary to maintain the quality of those medicinal products;

(e) ensure that any arrangements he makes with any person for the storageand distribution of the medicinal products are adequate to maintain thequality of those products;

(f) not use any premises for the handling, control, storage or distributionof relevant medicinal products other than those specified in his licenceas approved by the licensing authority for that purpose, or approvedby the licensing authority for that purpose from time to time;


(g) inform the licensing authority before making any material alterationin the premises or facilities used under his licence, or in the operationsfor which they are used;

(h) inform the licensing authority of any change that he proposes to maketo any personnel named in his licence as responsible for quality controlof the medicinal products being imported by him including the personnamed as the qualified person for the purposes of regulation 4;

(i) for the purpose of enabling the licensing authority to ascertain whetherthere are any grounds:(i) for suspending, revoking or varying any licence granted under

Part II of the Act; or(ii) suspending or terminating any licence in accordance with the provi-

sions of Part II of the Act, permit, and provide all necessary facilitiesto enable, any person duly authorised in writing by the licensingauthority, on production if required of his credentials, to carry outsuch inspection or to take such samples or copies, in relation tothings belonging to, or any business carried on by, the holder of thelicence, as such person would have the right to carry out or takeunder the Act for the purpose of verifying any statement containedin an application for a licence; and

(j) where he distributes by way of wholesale dealing, any relevantmedicinal product manufactured or assembled pursuant to his licence,comply with the requirements of regulations 8(1)(a) and (b) and(2), and 9 (2) and (3), as if he was the holder of a wholesale dealer’slicence.

Requirements as to qualified persons

4 (1) Subject to paragraphs (7) and (8), where a manufacturer’s licence relatesto the manufacture, assembly or importation of relevant medicinalproducts, a manufacturer’s licence holder shall ensure that he has atall times at his disposal the services of at least one qualified personwho is responsible for carrying out, in relation to those products,the duties specified in Article 51 of the Directive in respect of rele-vant medicinal products manufactured, assembled or imported byhim.

(2) If a licence holder satisfies the requirements as to qualifications andexperience specified in the definition of “qualified person” in regulation1(2), he may act as the qualified person in accordance with paragraph(1) for the purposes of that licence.

(3) For the purposes of this paragraph, but without prejudice to para-graph (4) below, the licence holder may regard a person as satisfying


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the provisions of Article 49 or 50 of the Directive as respects formalqualifications if he produces evidence that:(a) he is a member of:

(i) the Institute of Biology,(ii) the Pharmaceutical Society,(iii) the Royal Society of Chemistry, or(iv) such other body as may appear to the licensing authority to be

an appropriate body for the purpose of this paragraph; and(b) he is regarded by the body of which he is a member as so satisfying

those provisions.(4) The licence holder:

(a) shall notify the licensing authority of the name and address anddegrees, diplomas or qualifications and experience of the personwho will carry out the functions of qualified person;

(b) shall notify the licensing authority of any change to the qualifiedperson; and

(c) shall not permit any person to act as qualified person other thanthe person named in his licence as qualified person or, subject toparagraph (5), any other such person whose name is notified to thelicensing authority.

(5) Where, after giving the licence holder and the person acting as a quali-fied person the opportunity of making representations to them (orallyor in writing), the licensing authority is of the opinion that:(a) the person so acting does not satisfy:

(i) the provisions of Articles 49 and 50 of the Directive as respectsqualifications and experience, or

(ii) the requirements as to qualifications and experience specifiedin paragraph (b) of the definition of “qualified person” inregulation 1(2); or

(b) he is failing to carry out the duties referred to in paragraph (1)adequately or at all, and has notified the licence holder accordinglyin writing, the licence holder shall not permit that person to act asa qualified person.

(6) Subject to paragraph (7), the licence holder shall at all times provide andmaintain such staff, premises, equipment and facilities as will enablethe qualified person who is at his disposal pursuant to paragraph (1),to carry out the duties referred to in that subsection.

(7) A licence holder shall not be required to meet the requirements of thisregulation in relation to any activity carried out pursuant to his licencewhich consists of the manufacture, assembly or import from a thirdcountry of relevant medicinal products pursuant to a manufacturer’slicence insofar as such activity is limited to the manufacture, assemblyor importation of:


(a) exempt relevant medicinal products; or(b) products which may be placed on the market in any EEA State

without a marketing authorization by virtue of legislation adoptedby that State under Article 5(2) of the Directive.

(8) Where the conditions specified in paragraph 2 of Article 51 of theDirective are satisfied, a qualified person shall not be required to meetthe requirements of point (b) of the first subparagraph of paragraph 1of Article 51 of the Directive in respect of the import of any relevantmedicinal product from a third country.

Offence relating to the sale and supply of starting materials for use in themanufacture of relevant medicinal products

5 (1) Any person who, in the course of a business carried on by him, sellsor supplies any active substance in circumstances where the activesubstance:(a) has not been manufactured in accordance with the principles

of good manufacturing practice applicable to starting materials;and

(b) is intended to be used by the person to whom it is sold or sup-plied in the manufacture of a relevant medicinal product otherthan an exempt relevant medicinal product, shall be guilty of anoffence.

(2) It shall be a defence to an offence under paragraph (1) for the personwho sells or supplies the relevant medicinal product in question toshow that he could not, by reasonable diligence have discovered thatit was not manufactured in accordance with the principles of goodmanufacturing practice applicable to starting materials.

(3) A person guilty of an offence under paragraph (1) shall be liable:(a) on summary conviction to a fine not exceeding the statutory maxi-

mum or to imprisonment for a term not exceeding three months orto both; or

(b) on conviction on indictment to a fine or to imprisonment for a termnot exceeding two years or to both.

Additional standard provisions for manufacturer’s licences which relate tovaccines, toxins and sera

7 (1) In addition to the standard provisions for manufacturer’s licences setout in Schedules 1 and 2, there shall be the following additional stan-dard provisions for manufacturer’s licences, insofar as those licencesrelate to relevant medicinal products which are vaccines for humanuse:


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(a) for all vaccines, including smallpox and BCG vaccines, those pro-visions set out in Part 1 of Schedule 3;

(b) for smallpox vaccine, those provisions set out in Part 2 of Schedule3; and

(c) for BCG vaccine, those provisions set out in Part 3 of Schedule 3.(2) In addition to the standard provisions for manufacturer’s licences set

out in Schedules 1 and 2, there shall be the following additional stan-dard provisions for manufacturer’s licences relating to relevant medi-cinal products which are toxins and sera for human use:(a) for toxins, those provisions set out in Part 4 of Schedule 3; and(b) for sera, those provisions set out in Part 5 of Schedule 3.

Schedule 1 of the Regulations

Standard provisions which may be incorporated in a manufacturer’slicence relating to the manufacture and assembly of relevantmedicinal products

1 The manufacturer’s licence holder shall place the quality control systemreferred to in Article 11(1) of Commission Directive 2003/94/EC underthe authority of the person notified to the licensing authority in accordancewith paragraph 7(2) of Schedule 1 to the Applications Regulations as beingresponsible for quality control.

2 The manufacturer’s licence holder may use a contract laboratory pursuantto Article 11(2) of Commission Directive 2003/94/EC if operated by aperson approved by the licensing authority.

3 The manufacturer’s licence holder shall provide such information as maybe requested by the licensing authority:

(a) about the products currently being manufactured or assembled underhis authorisation; and

(b) about the operations being carried out in relation to such manufactureor assembly.

4 The manufacturer’s licence holder shall inform the licensing authority ofany change that he proposes to make to any personnel named in his licenceas respectively:

(a) responsible for supervising the production operations;(b) in charge of the animals from which are derived any substances used

in the production of the medicinal products being manufactured orassembled; or


(c) responsible for the culture of any living tissues used in the manufactureof the medicinal products being manufactured or assembled.

5 The manufacturer’s licence holder shall:

(a) keep readily available for inspection by a person authorised by thelicensing authority the batch documentation referred to in Article 9(1)of Commission Directive 2003/94/EC; and

(b) permit the person authorised to take copies or make extracts from suchdocumentation.

6 The manufacturer’s licence holder shall keep readily available for examina-tion by a person authorised by the licensing authority, the samples of eachbatch of finished relevant medicinal product referred to in Article 11(4) ofCommission Directive 2003/94/EC.

7 Where the manufacturer’s licence holder has been informed by the licensingauthority that any batch of any relevant medicinal product to which hislicence relates has been found not to conform as regards strength, qualityor purity with:

(a) the specification of the relevant product; or(b) the provisions of these Regulations, the Act or any other Regulations

under the Act that are applicable to the relevant medicinal product,he shall, if so directed, withhold such batch from distribution, so faras may be reasonably practicable, for such a period not exceeding sixweeks as may be specified by the licensing authority.

8 The manufacturer’s licence holder shall ensure that any tests for deter-mining conformity with the standards and specifications applying to anyparticular product used in the manufacture of a relevant medicinal productshall, except so far as the conditions of the product specification for thatproduct otherwise provide, be applied to samples taken from the medici-nal product after all manufacturing processes have been completed, or atsuch earlier stage in the manufacture as may be approved by the licensingauthority.

9 Where the manufacturer’s licence relates to the assembly of any rele-vant medicinal product or class of product, and the licence holder sup-plies that relevant medicinal product at such a stage of assembly thatdoes not fully comply with the provisions of the product specificationthat relate to labelling, the licence holder shall communicate the partic-ulars of those provisions to the person to whom that product has been sosupplied.


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10 Where:

(a) the manufacturer’s licence relates to the assembly of a relevant medi-cinal product;

(b) that medicinal product is not manufactured by the licence holder; and(c) particulars as to the name and address of the manufacturer of, or of the

person who imports, that relevant medicinal product have been givenby the licence holder to the licensing authority, the licence holder shallforthwith notify the licensing authority in writing of any changes insuch particulars.

11 The licence holder shall keep readily available for examination by a per-son authorised by the licensing authority durable records of the details ofmanufacture of any intermediate products held by him which are for usein the manufacture of biological medicinal products for human use, andthese records shall:

(a) be in such form as to ensure that the licence holder has a comprehensiverecord of all matters that are relevant to an evaluation of the safety,quality and efficacy of any finished biological medicinal product forhuman use which he manufactures using those intermediate products;and

(b) not be destroyed without the consent of the licensing authority untilthe records of the details of manufacture of any finished medicinalproducts which were or may be manufactured using those intermediateproducts may be destroyed in accordance with the requirements of theseRegulations.

12 Where:

(a) animals are used in the production of any medicinal products; and(b) relevant marketing authorizations contain provisions relating to them,

the manufacturer’s licence holder shall arrange for those animals to behoused in premises of such a nature, and be managed in such a manner asto facilitate compliance with such provisions.

13 The licence holder shall take all reasonable precautions and exercise alldue diligence to ensure that any information he provides to the licensingauthority which is relevant to an evaluation of the safety, quality or efficacyof:

(a) any medicinal product for human use which he manufactures or assem-bles; or

(b) any starting materials or intermediate products that he holds which arefor use in the manufacture of relevant medicinal products, is not falseor misleading in any material particular.



Standard provisions which may be incorporated in a manufacturer’slicence relating to the import of relevant medicinal productsfrom a third country

1 The manufacturer’s licence holder shall place the quality control systemreferred to in Article 11(1) of Commission Directive 2003/94/EC underthe authority of the person notified to the licensing authority in accordancewith paragraph 7(2) of Schedule 1 to the Applications Regulations as beingresponsible for quality control.

2 The manufacturer’s licence holder may use a contract laboratory pursuantto Article 11(2) of Commission Directive 2003/94/EC if operated by aperson approved by the licensing authority.

3 The manufacturer’s licence holder shall provide such information as maybe requested by the licensing authority concerning the type and quantityof any medicinal products which he imports.

4 The manufacturer’s licence holder shall:

(a) keep readily available for inspection by a person authorised by thelicensing authority the batch documentation referred to in Article 9(1)of Commission Directive 2003/94/EC; and

(b) permit the person authorised to take copies or make extracts from suchdocumentation.

5 Where the manufacturer’s licence holder has been informed by the licensingauthority that any batch of any medicinal product to which his licencerelates has been found not to conform as regards strength, quality or puritywith:

(a) the specification of the relevant product; or(b) the provisions of these Regulations, the Act or any regulations under

the Act that are applicable to the investigational medicinal product,he shall, if so directed, withhold such batch from distribution, so faras may be reasonably practicable, for such a period not exceeding sixweeks as may be specified by the licensing authority.

6 The manufacturer’s licence holder shall ensure that any tests for deter-mining conformity with the standards and specifications applying to anyparticular product used in the manufacture of a relevant medicinal productshall, except so far as the conditions of the product specification for thatproduct otherwise provide, be applied to samples taken from the medici-nal product after all manufacturing processes have been completed, or at


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such earlier stage in the manufacture as may be approved by the licensingauthority.

7 (1) Where and insofar as the licence relates to relevant medicinal productsto which paragraph 1 of Schedule 1 to the 1994 regulations applies,the licence holder shall only import such products from a third coun-try:(a) in response to an order which satisfies the requirements of

paragraph 1 of Schedule 1 to the 1994 Regulations; and(b) where the conditions set out in sub-paragraphs (2) to (9) are

complied with.(2) No later than 28 days prior to each importation of an exempt

imported product, the licence holder shall give written notice to thelicensing authority stating his intention to import that medicinal prod-uct and stating the following particulars:(a) the name of the medicinal product, being the brand name or the

common name, or the scientific name, and any name, if different,under which the medicinal product is to be sold or supplied in theUnited Kingdom;

(b) any trademark or the name of the manufacturer of the medicinalproduct;

(c) in respect of each active constituent of the medicinal product, anyinternational non-proprietary name or the British approved nameor the monograph name or, where that constituent does not havean international non-proprietary name, a British approved nameor a monograph name, the accepted scientific name or any othername descriptive of the true nature of that constituent;

(d) the quantity of medicinal product which is to be imported whichshall not exceed the quantity specified in sub-paragraph (6);and

(e) the name and address of the manufacturer or assembler of thatmedicinal product in the form in which it is to be imported and, ifthe person who will supply that medicinal product for importationis not the manufacturer or assembler, the name and address of suchsupplier.

(3) Subject to sub-paragraph (4), the licence holder shall not import theexempt imported product if, before the end of 28 days from the dateon which the licensing authority sends or gives the licence holder anacknowledgement in writing by the licensing authority that they havereceived the notice referred to in sub-paragraph (2) above, the licens-ing authority have notified him in writing that the product should notbe imported.

(4) The licence holder may import the exempt imported product referredto in the notice where he has been notified in writing by the


licensing authority, before the end of the 28-day period referred toin sub-paragraph (3), that the exempt imported product may beimported.

(5) Where the licence holder sells or supplies exempt imported products,he shall, in addition to any other records which he is required by theprovisions of his licence to make, make and maintain written recordsrelating to:(a) the batch number of the batch of the product from which the sale

or supply was made; and(b) details of any adverse reaction to the product so sold or supplied

of which he becomes aware.(6) The licence holder shall import no more on any one occasion than

such amount as is sufficient for 25 single administrations, or for 25courses of treatment where the amount imported is sufficient for amaximum of three months’ treatment, and on any such occasion shallnot import more than the quantity notified to the licensing authorityunder sub-paragraph (2)(d).

(7) The licence holder shall inform the licensing authority forthwith ofany matter coming to his attention which might reasonably cause thelicensing authority to believe that the medicinal product can no longerbe regarded either as a product which can safely be administered tohuman beings or as a product which is of satisfactory quality for suchadministration.

(8) The licence holder shall not issue any advertisement, catalogue, pricelist or circular relating to the exempt relevant medicinal product ormake any representations in respect of that product.

(9) The licence holder shall cease importing or supplying an exemptimported product if he has received a notice in writing from the licens-ing authority directing that, as from a date specified in that notice, aparticular product or class of products shall no longer be imported orsupplied.

(10) In this paragraph:

“British approved name” means the name which appears in the cur-rent edition of the list prepared by the appropriate body in accor-dance with Section 100 of the Act and published by the Ministerson the recommendation of the Commission and “current” in thisdefinition means current at the time the notice is sent to the licens-ing authority;

“common name” means the international non-proprietary name or,if one does not exist, the usual common name;

“international non-proprietary name” means a name which has beenselected by the World Health Organization as a recommendedinternational non-proprietary name and in respect of which the


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Director-General of the World Health Organization has givennotice to that effect in the World Health Organization Chronicle;and

“monograph name” means the name or approved synonym whichappears at the head of a monograph in the current edition ofthe British Pharmacopoeia, the British Pharmaceutical Codex,the European Pharmacopoeia or a foreign or international com-pendium of standards and “current” in this definition meanscurrent at the time the notice is sent to the licensing authority.

8 The licence holder shall take all reasonable precautions and exercise alldue diligence to ensure that any information he provides to the licensingauthority which is relevant to an evaluation of the safety, quality or efficacyof any medicinal product for human use which he imports from a thirdcountry, handles, stores or distributes is not false or misleading in a materialparticular.


Standard provisions which may be incorporated in a manufacturer’slicence which relates to vaccines

1 (1) The licence holder shall provide separate premises or separate parts ofpremises referred to in this Part as “the designated premises,” for theactivities specified in the following sub-paragraphs, namely:(a) the production and the testing involved in the production of cell

cultures for use in the production of vaccine;(b) the production and the testing involved in the production of vaccine

prepared from viruses; and(c) the production and the testing involved in the production of vac-

cine prepared from micro-organisms or detoxified microbial toxins,and shall ensure that only persons necessary to each of the abovementioned activities shall have access to the designated premisesprovided for that activity.

2 The licence holder shall ensure that any procedure which, in the course ofany of the activities specified in the preceding paragraph involves or mightinvolve:

(a) the presence of transmissible agents; or(b) the use of cell cultures, animal tissues or micro-organisms, other than

those from which the vaccine is produced, shall not be carried out inthe designated premises referred to in paragraph 1.


3 The licence holder shall ensure that no person who has been in contact withtransmissible agents or experimental animals (other than those connectedwith the vaccine being produced in the designated premises referred to inparagraph 1) shall enter the designated premises on the same day that suchcontact has occurred.

4 Before an animal is used in the production of a vaccine, the licence holdershall take all reasonable steps to ensure that it is free from disease, andto that end shall keep the animal in quarantine and under observation forsuch period as the licensing authority may specify.

5 The licence holder shall ensure:

(a) that animals used in the production of vaccine are isolated and shallprovide separate premises (not being the designated premises referredto in paragraph 1) for this purpose; and

(b) that only persons engaged in the production and testing of vaccinesor in the maintenance of animals or premises shall have access to theseparate premises in which the animals are isolated.

6 The licence holder shall provide a separate room in the premises referredto in paragraph 5 which is capable of being washed and disinfected andwhich is to be used for the purpose of:

(a) the inoculation of animals; and(b) the collection of material to be used in the preparation of vaccine.

7 Without prejudice to any other requirements to keep records, where vac-cines contain or might contain micro-organisms or microbial toxins, thelicence holder shall keep a durable record, readily available for inspec-tion by a person authorised by the licensing authority, of the origin,properties and characteristics of the cell cultures used in the produc-tion of those vaccines and shall ensure that that record is not destroyedfor a period of five years from the date when the relevant productionoccurred.

8 Nothing in this Schedule shall operate so as to restrict the right of accessto any premises of any person who is duly authorised by the enforcementauthority to enter those premises in accordance with section 111 of theAct.

Standard provisions which may be incorporated in a manufacturer’slicence which relates to smallpox vaccines

1 The licence holder shall ensure that animals used in the production ofsmallpox vaccine:


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(a) shall only be inoculated on a part of the skin that has beendepilated and cleansed and which cannot be soiled by urine or faeces,and

(b) are kept under observation for 28 days after the collection of the vac-cinal material.

2 Should any animal during the 28 day period referred to in paragraph1 be found to be suffering from any infection other than vaccinia orshow serious or persistent signs of ill health, vaccinal material obtainedfrom that animal shall not be used in the production of smallpoxvaccine.

3 Where it is necessary for an animal which has been inoculated for use inthe production of smallpox vaccine to be killed, the licence holder shallensure that:

(a) the vaccinal material is collected immediately after the animal has beenkilled;

(b) if the licensing authority so directs, a post-mortem examination of thecarcass of the animal is made by a person with experience of the diseasesof the particular animal which has been killed;

(c) a durable record of the examination is made and retained for a periodof five years from the date when the animal was killed, and kept readilyavailable for inspection by a person authorised by the licensing author-ity; and

(d) where the examination indicates that the animal was suffering fromdiseases other than vaccinia, no vaccinal material obtained from thatanimal is used in the production of smallpox vaccine.

Standard provisions which may be incorporated in a manufacturer’slicence which relates to BCG vaccines

1 The licence holder shall provide separate premises or separate parts ofpremises for the production of BCG vaccine, and shall ensure that onlypersons necessary to the production and testing of that vaccine shall haveaccess to those separate premises or separate parts of premises.

2 The licence holder shall ensure that any procedure which involves or mightinvolve:

(a) the presence of transmissible agents other than BCG, or(b) the use of microbial cultures other than BCG, shall not be carried out

in the separate premises or separate parts of premises referred to inparagraph 1 of this Schedule.


3 The licence holder shall ensure that all media, glassware and other appa-ratus issued in the production of BCG vaccine shall be kept and preparedfor use in the separate premises or separate parts of premises referred to inparagraph 1 of this Part of this Schedule.

4 The licence holder shall not permit animals to be in the separate premisesor separate parts of premises referred to in paragraph 1 of this Part of thisSchedule and where it is necessary to use animals for testing BCG vaccine,the tests shall not be carried out in those separate premises or separateparts of premises.

5 (1) The licence holder shall arrange for all persons engaged in theproduction of BCG vaccine to be examined clinically by a doctorand where appropriate, radiologically and bacteriologically, at leastevery twelve months and whenever such a person shows signs of illhealth.

(2) The licence holder shall ensure (as far as paragraph (c) below is con-cerned, in so far as is reasonably practicable), that persons falling withinthe following descriptions shall not engage in the production of BCGvaccine, that is to say:(a) persons examined as aforesaid who are found to be suffering from

active or potentially active tuberculosis lesions,(b) persons who show a negative reaction when tested with tuberculin,

or(c) persons who are in close contact with a person who is suffering

from any active form of tuberculosis.(3) If on examination in accordance with subparagraph (1), a person

engaged in the production of BCG vaccine is found to be suffer-ing from active or potentially active tuberculosis lesions, then, afterthat person has been removed from the separate premises or sepa-rate parts of premises referred to in paragraph (1), the licence holdershall:(a) make arrangements for those separate premises or separate parts of

premises and all equipment used in the production of BCG vaccineto be treated in such a manner as to remove the risk of contamina-tion of the vaccine; and

(b) cease to use any unsealed cultures of BCG and all current prepara-tions of BCG vaccine which may have become contaminated withother Mycobacterium tuberculosis organisms.

6 The licence holder shall ensure that no person who has been in contactwith transmissible agents other than BCG vaccine shall enter the separatepremises or separate parts of premises referred to in paragraph 1 on thesame day that such contact has been made.


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Standard provisions which may be incorporated in a manufacturer’slicence which relates to toxins

1 The licence holder shall provide separate premises or separate parts ofpremises for the production and the testing involved in the productionof toxins and shall ensure that only persons necessary to the productionand testing of toxins (or related toxoids) shall have access to the separatepremises or separate parts of those premises.

2 Nothing in paragraph 1 shall operate so as to restrict the right of accessto any premises of any person who is duly authorised by the enforcementauthority to enter those premises in accordance with Section 111 of theAct.

3 The licence holder shall ensure that any procedure which in the course ofthe production and testing referred to in the previous paragraph involvesor might involve the presence of micro-organisms, plants or animals otherthan those from which the toxins are to be produced, shall not be carriedout in the separate premises or separate parts of premises referred to inparagraph 1.

Standard provisions which may be incorporated in a manufacturer’slicence which relates to sera

1 The licence holder shall ensure that blood used in the production of anyserum shall only be collected from living animals in separate premiseswhich:

(a) are used for no other purpose,(b) have impervious walls and floors, and(c) are capable of being washed and chemically disinfected.

2 The licence holder shall ensure that an adequate system of manure removalis in operation in the separate premises referred to in paragraph 1.

3 Before an animal is used in the production of any serum, the licence holdershall take all reasonable steps to ensure that it is free from disease andto this end shall keep the animal in quarantine and under observation forsuch period as the licensing authority may direct.

4 The licence holder shall notify the licensing authority if any animal whichhas been used in the production of any serum is found to be suffering froman infection other than an infection produced by living organisms againstwhich it is being immunised or shows serious or persistent signs of ill-health not attributable to the process of immunisation and shall withhold


any serum obtained from that animal from sale, supply or exportationuntil he has obtained the consent of the licensing authority in writing to itsrelease.

5 The licence holder shall notify the licensing authority if any post-mortemexamination on any animal indicates that any other animals used in theproduction of any serum are or are likely to be unhealthy, and the licenceholder shall not use those animals for the production of any serum untileither he has obtained the consent of the licensing authority in writing orhas complied with any requirements the licensing authority may considernecessary in the interest of safety.

6 The licence holder shall ensure that laboratories in which any serum isprocessed are separate from premises in which animals are housed.

7 The licence holder shall provide such number of sterilizers as are neces-sary for the sterilization of all glassware and other apparatus used in theproduction of sera.

8 Without prejudice to any other requirements to keep records, the licenceholder shall keep the following durable records relating to the produc-tion of sera readily available for inspection by a person authorised by thelicensing authority, and shall ensure that those records are not destroyedfor a period of five years from the date when the relevant productionoccurred:

(a) as to the cultures used:(i) the source from which the culture was obtained,(ii) the nature of the material from which the culture was isolated,(iii) the date of the isolation, and(iv) evidence of the identity and specificity of the culture;

(b) as to the procedure used in the immunizing of animals:(i) the method of preparing the culture or antigen used for immuniza-

tion,(ii) the dosage and methods employed in administering the culture or

antigen, and(iii) the time in the course of immunization at which blood is with-

drawn for preparation of the serum; and(c) the results of any tests which may have been applied to the serum to

determine its content of specific antibodies or its specific therapeuticpotency.

9 Nothing in this Part shall operate so as to restrict the right of access toany premises of any person who is duly authorised by the enforcementauthority to enter those premises in accordance with section 111 of theAct.


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Prescribed Conditions for Manufacturer’s Undertakings for ImportedProducts (SI 1977 No. 1038)

Extract from: The Medicines (Manufacturer’s Undertakings for ImportedProducts) Regulations 1977 (SI 1977 No. 1038) as amended by SI 1992No. 2845 and SI 2005/2745.

Editor’snote

This extract from the Regulations is presented for the reader’s convenience.For any definitive information reference must be made to the originalRegulations.

An additional Regulation (Regulation 1A) is inserted by SI 2005 No. 2745to exclude veterinary medicinal products; and Regulation 4 is inserted bySI 1992 No. 2845 to exclude from the scope of the Regulations applicationsfor products coming from another Member State of the EU.

Schedule

Prescribed conditions for manufacturer’s undertakings

1 The manufacturer shall provide and maintain such staff, premises, andplant as are necessary for the carrying out in accordance with the relevantproduct licences of such stages of the manufacture and assembly of themedicinal products to which the relevant product licences relate as areundertaken by him.

2 The manufacturer shall provide and maintain such staff, premises, equip-ment and facilities for the handling, storage and distribution of the medici-nal products to which the relevant product licences relate which he handles,stores or distributes as are necessary to avoid deterioration of the medicinalproducts.

2A In relation to medicinal products for human use, the manufacturer shallprovide and maintain a designated quality control department havingauthority in relation to quality control and being independent of all otherdepartments.

3 The manufacturer shall conduct all manufacture and assembly operationsin such a way as to ensure that the medicinal products to which the relevantproduct licences relate conform with the standards of strength, quality andpurity applicable to them under the relevant product licences.


3A In relation to medicinal products for human use, the manufacturer shallmaintain an effective pharmaceutical quality assurance system involvingthe active participation of the management and personnel of the differentservices involved.

4 Where animals are used in the production of any medicinal product andthe relevant product licences contain provisions relating to them the man-ufacturer shall arrange for the animals to be housed in premises of such anature and to be managed in such a way as will facilitate compliance withsuch provisions.

5 The manufacturer shall make such adequate and suitable arrangementsas are necessary for carrying out in accordance with the relevant productlicences any tests of the strength, quality or purity of the medicinal productsto which the licences relate.

6 The manufacturer shall inform the holder of the relevant product licences ofany material alteration in the premises or plant used in connection with themanufacture or assembly of the medicinal products to which the relevantproduct licences relate or in the operations for which such premises or plantare so used and of any change, since the granting of the relevant productlicences in respect of any person:

(a) responsible for supervising the production operations, or(b) responsible for quality control of the medicinal products to which the

relevant product licences relate, or(c) in charge of the animals from which are derived any substance used in

the production of the medicinal products to which the relevant productlicences relate, or

(d) responsible for the culture of any living tissues used in the manufactureof the medicinal products to which the relevant product licences relate.

7 The manufacturer shall keep readily available for inspection by a personauthorised by the licensing authority durable records of the details ofmanufacture and assembly of each batch of every medicinal product towhich each relevant product licence relates and of the tests carried outthereon in such a form that the records will be easily identifiable from thenumber of the batch as shown on each container in which the medicinalproduct is exported from the country where it has been manufactured orassembled; the manufacturer shall permit the person authorised to takecopies of or make extracts from such records. Such records shall not bedestroyed:

(a) in relation to a medicinal product for human use, for a period of fiveyears from the date of release of the relevant batch, or for a period ofone year after the expiry date of the relevant batch, whichever expireslater,


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(b) in any other case, for a period of five years from the date when themanufacture or assembly of the relevant batch of the medicinal productoccurred.

7A In relation to medicinal products for human use to which a product licencerelates, the manufacturer shall keep readily available for examination by aperson authorised by the licensing authority, samples of:

(a) each batch of finished products for at least a period of one year aftertheir expiry date; and

(b) starting materials (other than solvents, gases or water) for at least aperiod of two years after release of the medicinal product of which therelevant starting materials formed part;

except where the manufacturer is authorised by the licensing authority todestroy such samples earlier.

7B (1) The manufacturer shall implement a system for recording and review-ing complaints in relation to medicinal products for human use to whicha product licence relates together with an effective system for recallingpromptly and at any time the medicinal products in the distributionnetwork.

(2) The manufacturer shall record and investigate all complaints describedin sub-paragraph (1) of this paragraph and shall immediately informthe licensing authority of any defect which could result in a recall fromsale, supply or exportation or in an abnormal restriction on such sale,supply or exportation.

8 The manufacturer shall inform the holder of the relevant product licenceof any material change since the date upon which such licence was grantedin respect of:

(a) the facilities and equipment available at each of the premises of themanufacturer for carrying out any stage of the manufacture or assemblyof the medicinal products to which the relevant product licences relate,or

(b) the facilities and equipment available in each of the premises of themanufacturer for the storage of the medicinal products to which therelevant product licences relate on, and distribution of the productsfrom or between, such premises, or

(c) any manufacturing operations, not being operations in relation to themedicinal products to which the relevant product licences relate, whichare carried on by the manufacturer on or near any of the premises onwhich such medicinal products are manufactured or assembled and thesubstances or articles in respect of which such operations are carriedon, or


(d) the arrangements for the identification and storage of materials andingredients before and during manufacture of the medicinal products towhich the relevant product licences relate and the arrangements for thestorage of the medicinal products after they have been manufacturedor assembled, or

(e) the arrangements for ensuring a satisfactory turnover of stocks ofmedicinal products to which the relevant product licences relate, or

(f) the arrangements for maintaining production records and records ofanalytical and other testing procedures applied in the course of manu-facture or assembly of the medicinal products to which the relevantproduct licences relate, or

(g) the arrangements for keeping reference samples of materials used in themanufacture of any medicinal products to which the relevant productlicences relate and reference samples of such medicinal products.

SECTION

IV

GUIDANCE ONWHOLESALEDISTRIBUTIONPRACTICE

CHAPTER

6

EU Guidance on WholesaleDistribution Practice

Contents

Guidelines on Good DistributionPractice of Medicinal Products forHuman Use (94/C 63/03) 341

Introduction 341Principle 341Personnel 342Documentation 343Orders 343Procedure 343Records 343Premises and equipment 344Receipt 344

Storage 344Deliveries to customers 345Returns 345Returns of non-defective medicinal

products 345Emergency plan and recalls 346Counterfeit medicinal products 346Special provisions concerning products

classified as not for sale 347Self inspections 347Provision of information to Member

States in relation to wholesaleactivities 347

GUIDELINES ON GOOD DISTRIBUTION PRACTICE OFMEDICINAL PRODUCTS FOR HUMAN USE (94/C 63/03)

Introduction

These guidelines have been prepared in accordance with Article 10 of Coun-cil Directive 92/25/EEC of 31 March 1992 on the wholesale distributionof medicinal products for human use1. They do not cover commercial rela-tionships between parties involved in distribution of medicinal productsnor questions of safety at work.

Principle

The Community pharmaceutical industry operates at a high level of qual-ity assurance, achieving its pharmaceutical quality objectives by observing

1 OJ No L 113, 30.4, 1992, p. 1.

341

342 IV GUIDANCE ON WHOLESALE DISTRIBUTION PRACTICE

Good Manufacturing Practice to manufacture medicinal products whichmust then be authorised for marketing. This policy ensures that productsreleased for distribution are of the appropriate quality.

This level of quality should be maintained throughout the distribu-tion network so that authorised medicinal products are distributed toretail pharmacists and other persons entitled to sell medicinal productsto the general public without any alteration of their properties. The con-cept of quality management in the pharmaceutical industry is describedin Chapter I of the Community Guide to Good Manufacturing Practicefor medicinal products and should be considered when relevant for thedistribution of medicinal products. The general concepts of quality man-agement and quality systems are described in the CEN standards (series29 000).

In addition, to maintain the quality of the products and the qual-ity of the service offered by wholesalers, Directive 92/25/EEC providesthat wholesalers must comply with the principles and guidelines ofgood distribution practice published by the Commission of the EuropeanCommunities.

The quality system operated by distributors (wholesalers) of medicinalproducts should ensure that medicinal products that they distribute areauthorised in accordance with Community legislation, that storage con-ditions are observed at all times, including during transportation, thatcontamination from or of other products is avoided, that an adequateturnover of the stored medicinal products takes place and that productsare stored in appropriately safe and secure areas. In addition to this, thequality system should ensure that the right products are delivered to theright addressee within a satisfactory time period. A tracing system shouldenable any faulty product to be found and there should be an effective recallprocedure.

Personnel

1 A management representative should be appointed in each distributionpoint, who should have defined authority and responsibility for ensuringthat a quality system is implemented and maintained. He should fulfil hisresponsibilities personally. This person should be appropriately qualified:although a degree in pharmacy is desirable, the qualification requirementsmay be established by the Member State on whose territory the wholesaleris located.

2 Key personnel involved in the warehousing of medicinal products shouldhave the appropriate ability and experience to guarantee that the productsor materials are properly stored and handled.


I VI V

3 Personnel should be trained in relation to the duties assigned to them andthe training sessions recorded.

Documentation

4 All documentation should be made available on request of competentauthorities.

Orders

5 Orders from wholesalers should be addressed only to persons authorisedto supply medicinal products as wholesalers in accordance with Article 3of Directive 92/25/EEC or holders of a manufacturing or importing au-thorisation granted in accordance with Article 16 of Directive 75/319/EEC.2

Procedures

6 Written procedures should describe the different operations which mayaffect the quality of the products or of the distribution activity: receipt andchecking of deliveries, storage, cleaning and maintenance of the premises(including pest control), recording of the storage conditions, security ofstocks on site and of consignments in transit, withdrawal from saleablestock, records, including records of clients orders, returned products, recallplans, etc. These procedures should be approved, signed and dated by theperson responsible for the quality system.

Records

7 Records should be made at the time each operation is taken and in sucha way that all significant activities or events are traceable. Records shouldbe clear and readily available. They should be retained for a period of fiveyears at least.

8 Records should be kept of each purchase and sale, showing the date ofpurchase or supply, name of the medicinal product and quantity receivedor supplied and name and address of the supplier or consignee. For trans-actions between manufacturers and wholesalers and between wholesalers(i.e. to the exclusion of deliveries to persons entitled to supply medicinalproducts to the public), records should ensure the traceability of the originand destination of products, for example by use of batch numbers, so thatall the suppliers of, or those supplied with, a medicinal product can beidentified.

2 OJ No L 147, 9.6, 1975, p. 13.


Premises and equipment

9 Premises and equipment should be suitable and adequate to ensure properconservation and distribution of medicinal products. Monitoring devicesshould be calibrated.

Receipt

10 Receiving bays should protect deliveries from bad weather duringunloading. The reception area should be separate from the storage area.Deliveries should be examined at receipt in order to check that containersare not damaged and that the consignment corresponds to the order.

11 Medicinal products subject to specific storage measures (e.g. narcotics,products requiring a specific storage temperature) should be immediatelyidentified and stored in accordance with written instructions and withrelevant legislative provisions.

Storage

12 Medicinal products should normally be stored apart from other goodsand under the conditions specified by the manufacturer in order to avoidany deterioration by light, moisture or temperature. Temperature shouldbe monitored and recorded periodically. Records of temperature shouldbe reviewed regularly.

13 When specific temperature storage conditions are required, storage areasshould be equipped with temperature recorders or other devices that willindicate when the specific temperature range has not been maintained.Control should be adequate to maintain all parts of the relevant storagearea within the specified temperature range.

14 The storage facilities should be clean and free from litter, dust and pests.Adequate precautions should be taken against spillage or breakage, attackby micro-organisms and cross-contamination.

15 There should be a system to ensure stock rotation (“first in first out”)with regular and frequent checks that the system is operating correctly.Products beyond their expiry date or shelf life should be separated fromusable stock and neither sold nor supplied.

16 Medicinal products with broken seals, damaged packaging, or suspectedof possible contamination should be withdrawn from saleable stock, andif not immediately destroyed, they should be kept in a clearly separatedarea so that they cannot be sold in error or contaminate other goods.


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Deliveries to customers

17 Deliveries should be made only to other authorised wholesalers or topersons authorised to supply medicinal products to the public in theMember State concerned.

18 For all supplies to a person authorised or entitled to supply medicinal prod-ucts to the public, a document must be enclosed, making it possible to ascer-tain the date, the name and pharmaceutical form of the medicinal product,the quantity supplied, the name and address of the supplier and addressee.

19 In case of emergency, wholesalers should be in a position to supplyimmediately the medicinal products that they regularly supply to thepersons entitled to supply the products to the public.

20 Medicinal products should be transported in such a way that:

(a) their identification is not lost;(b) they do not contaminate, and are not contaminated by, other products

or materials;(c) adequate precautions are taken against spillage, breakage or theft;(d) they are secure and not subjected to unacceptable degrees of heat,

cold, light, moisture or other adverse influence, nor to attack bymicro-organisms or pests.

21 Medicinal products requiring controlled temperature storage should alsobe transported by appropriately specialised means.

Returns

Returns of non-defective medicinal products

22 Non-defective medicinal products which have been returned should bekept apart from saleable stock to prevent redistribution until a decisionhas been reached regarding their disposal.

23 Products which have left the care of the wholesaler, should only bereturned to saleable stock if:

(a) the goods are in their original unopened containers and in goodcondition;

(b) it is known that the goods have been stored and handled under properconditions;

(c) the remaining shelf life period is acceptable;(d) they have been examined and assessed by a person authorised to do so.

This assessment should take into account the nature of the product,


any special storage conditions it requires, and the time elapsed sinceit was issued. Special attention should be given to products requiringspecial storage conditions. As necessary, advice should be sought fromthe holder of the marketing authorisation or the Qualified Person ofthe manufacturer of the product.

24 Records of returns should be kept. The responsible person should formallyrelease goods to be returned to stock. Products returned to saleable stockshould be placed such that the “first in first out” system operates effectively.

Emergency plan and recalls

25 An emergency plan for urgent recalls and a non-urgent recall proced-ure should be described in writing. A person should be designated asresponsible for execution and co-ordination of recalls.

26 Any recall operation should be recorded at the time it is carried out andrecords should be made available to the competent authorities of theMember States on whose territory the products were distributed.

27 In order to ensure the efficacy of the emergency plan, the system ofrecording of deliveries should enable all destinees of a medicinal productto be immediately identified and contacted. In case of recall, wholesalersmay decide to inform all their customers of the recall or only those havingreceived the batch to be recalled.

28 The same system should apply without any difference to deliveries in theMember States having granted the authorisation for wholesaling and inother Member States.

29 In case of batch recall, all customers (other wholesalers, retail or hospitalpharmacists and persons entitled to sell medicinal products to the public)to whom the batch was distributed should be informed with the appro-priate degree of urgency. This includes customers in other Member Statesthan the Member State having granted the wholesaling authorisation.

30 The recall message approved by the holder of the marketing authorisation,and, when appropriate, by the competent authorities, should indicatewhether the recall should be carried out also at retail level. The messageshould request that the recalled products be removed immediately from thesaleable stock and stored separately in a secure area until they are sent backaccording to the instructions of the holder of the marketing authorisation.

Counterfeit medicinal products

31 Counterfeit medicinal products found in the distribution network shouldbe kept apart from other medicinal products to avoid any confusion. They


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should be clearly labelled as not for sale and competent authorities andthe holder of marketing authorisation of the original product should beinformed immediately.

Special provisions concerning products classified as not for sale

32 Any return, rejection, and recall operation and receipt of counterfeit prod-ucts should be recorded at the time it is carried out and records should bemade available to the competent authorities. In each case, a formal decisionshould be taken on the disposal of these products and the decision shouldbe documented and recorded. The person responsible for the qualitysystem of the wholesaler and, where relevant, the holder of the marketingauthorisation should be involved in the decision making process.

Self inspections

33 Self-inspections should be conducted (and recorded) in order to monitorthe implementation of and compliance with this guideline.

Provision of information to Member States in relation towholesale activities

34 Wholesalers wishing to distribute or distributing medicinal products inMember State(s) other than the Member State in which the authorisationwas granted should make available on request to the competent author-ities of the other Member State(s) any information in relation to theauthorisation granted in the Member State of origin, namely the natureof the wholesaling activity, the address of sites of storage and distributionpoint(s) and, if appropriate, the area covered. Where appropriate, thecompetent authorities of this (these) other Member State(s) will informthe wholesaler of any public service obligation imposed on wholesalersoperating on their territory.

CHAPTER

7

UK Guidance on WholesaleDistribution Practice

Contents

Wholesale Dealer’s Obligations 349Appointment and Duties of the

Responsible Person 355Control and Monitoring of Storage

and TransportationTemperatures 357

Introduction 357Cold storage 357Controlled room temperature

storage 358Transportation 358Counterfeits/Ensuring Bona

Fides 359

Diverted Medicines 360Parallel Distribution 361Relabelling/repackaging 362Maintenance of the integrity of the

supply chain 363Continued Supply 363Product Recall/Withdrawal 366Issue a “recall” 366Issue a “Drug Alert” 367Management of the recall 367Follow-up action 367Reporting a suspected defect 368

Wholesale Dealer’s Obligations

The holder of a wholesale dealer’s licence must comply with certain obliga-tions in relation to the wholesale distribution of relevant medicinal prod-ucts. These obligations are set out in Regulations 8–11 of The Medicinesfor Human Use (Manufacturing, Wholesale Dealing and MiscellaneousAmendments) Regulations 2005 [SI 2005/2789]. They require that thelicence holder shall:

(a) comply with the guidelines on Good Distribution Practice (GDP);1

(b) ensure, within the limits of his responsibility as a distributor of rele-vant medicinal products, the appropriate and continued supply of such

1 Guidelines on Good Distribution Practice (GDP) of medicinal products forhuman use (94/C63/03) and Rules and Guidance for Pharmaceutical Manufac-turers and Distributors.

349


relevant medicinal products to pharmacies and persons who may law-fully sell such products by retail or who may lawfully supply them incircumstances corresponding to retail sale;

(c) provide and maintain such staff, premises, equipment and facilities forthe handling, storage and distribution of the relevant medicinal prod-ucts which he handles, in accordance with his licence as are necessary tomaintain the quality of, and ensure proper distribution of the medicinalproducts (see Control and Monitoring of Storage and TransportationTemperatures);

(d) inform the licensing authority of any proposed structural alteration to,or discontinued use of, premises to which the licence relates or premiseswhich have been approved by the licensing authority;

(e) inform the licensing authority of the name and address and degrees,diplomas or qualifications and experience of the person who will carryout the functions of responsible person;

(f) inform the licensing authority of any change to the responsible person.

The holder of a wholesale dealer’s licence shall not sell or offer for sale orsupply any relevant medicinal product unless:

(a) there is a marketing authorisation for the time being in force in respectof that product; and

(b) the sale or offer for sale is in accordance with the provisions of thatauthorisation.

The restrictions on the holder of a wholesale dealer’s licence shall not applyto:

(a) the sale or offer for sale of any exempt relevant medicinal product;and

(b) the export to an EEA State, or supply for the purposes of such export,of a relevant medicinal product which may be placed on the marketin that State without a marketing authorisation by virtue of legislationadopted by that State under Article 5(2) of Directive 2001/83/EC, asamended.

The holder of a wholesale dealer’s licence shall:

(a) keep such documents relating to the sale of medicinal products to whichhis licence relates as will facilitate the withdrawal or recall from saleof relevant medicinal products in accordance with paragraph (b);

(b) have in place an emergency plan which will ensure effective implemen-tation of the recall from the market of any relevant medicinal productswhere such recall is:(i) ordered by the licensing authority or by the competent authority of

any other EEA State; or


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(ii) carried out in co-operation with the manufacturer of, or the holderof the marketing authorisation for, the product in question;

(c) keep such records, which may be in the form of purchase and salesinvoices, or on a computer or in any other form, which give, as aminimum, where any relevant medicinal products are received or dis-patched, the following information:(i) the date of receipt or, as the case may be, dispatch,(ii) the name of the relevant medicinal product,(iii) the quantity received or, as the case may be, dispatched, and(iv) the name and address of, as may be applicable in each case, the

person from whom the products are received or to whom they aresold or supplied.

Where the holder of a wholesale dealer’s licence imports from another EEAState any relevant medicinal product in respect of which he is not eitherthe marketing authorisation holder in respect of that product; or acting onbehalf of the marketing authorisation holder in importing that product. Heshall notify the marketing authorisation holder and the licensing authorityof his intention to import it.

The licence holder, for the purpose of enabling the licensing authorityto ascertain whether there are any grounds:

(a) for suspending, revoking or varying any licence granted under Part IIof the Act; or

(b) suspending or terminating any licence in accordance with the provisionsof Part II of the Act, shall permit, and provide all necessary facilities toenable, any person duly authorised in writing by the licensing authority,on production if required of his credentials, to carry out such inspec-tion or to take such samples or copies, in relation to things belongingto, or any business carried on by, the holder of the licence, as suchperson would have the right to carry out or take under the Act for thepurpose of verifying any statement contained in an application for alicence.

The holder of a wholesale dealer’s licence shall obtain supplies of relevantmedicinal products only from:

(a) a manufacturer’s licence holder or wholesale dealer’s licence holder inrespect of such products; or

(b) a person who holds an authorisation granted by another EEA Stateauthorizing the manufacture of such products or their distribution byway of wholesale dealing.

The holder of a wholesale dealer’s licence shall distribute relevant medicinalproducts by way of wholesale dealing only to:

(a) a holder of a wholesale dealer’s licence relating to those products;


(b) a holder of an authorisation granted by the competent authority ofanother EEA State authorising the supply of those products by way ofwholesale dealing;

(c) any person who may lawfully sell those products by retail or who maylawfully supply them in circumstances corresponding to retail sale; or

(d) any person who may lawfully administer those products.

Where any relevant medicinal product is supplied to any person who maylawfully sell those products by retail or who may lawfully supply them incircumstances corresponding to retail sale, the licence holder shall enclosewith the product a document which makes it possible to ascertain:

(a) the date on which the supply took place;(b) the name and pharmaceutical form of the product supplied;(c) the quantity of product supplied; and(d) the names and addresses of the person or persons from whom the

products were supplied to the licence holder.

The licence holder shall:

(a) keep a record of the information supplied where any relevant medic-inal product is supplied to any person who may lawfully sell thoseproducts by retail or who may lawfully supply them in circumstancescorresponding to retail sale for a minimum period of five years afterthe date on which it is supplied; and

(b) ensure, during that period, that that record is available to the licensingauthority for inspection.

Where a wholesale dealer’s licence relates to relevant medicinal products,the wholesale dealer’s licence holder shall at all times have at his disposalthe services of a responsible person who, in the opinion of the licensingauthority:

(a) has knowledge of the activities to be carried out and of the proceduresto be performed under the licence which is adequate for performing thefunctions of responsible person; and

(b) has experience in those procedures and activities which is adequate forthose purposes.

The functions of the responsible person shall be to ensure, in relation torelevant medicinal products, that the conditions under which the licencehas been granted have been, and are being, complied with and the qualityof relevant medicinal products which are being handled by the wholesaledealer’s licence holder are being maintained in accordance with the require-ments of the marketing authorisations applicable to those products.

The standard provisions for wholesale dealer’s licences, that is, those pro-visions which may be included in all licences unless the licence specifically


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provides otherwise, insofar as those licences relate to relevant medicinalproducts, shall be those provisions set out in Schedule 4 of The Medicinesfor Human Use (Manufacturing, Wholesale Dealing and MiscellaneousAmendments) Regulations 2005 [SI 2005/2789].

The licence holder shall not use any premises for the purpose of thehandling, storage or distribution of relevant medicinal products other thanthose specified in his licence or notified to the licensing authority by himand approved by the licensing authority.

The licence holder shall provide such information as may be requestedby the licensing authority concerning the type and quantity of any relevantmedicinal products which he handles, stores or distributes.

Where and insofar as the licence relates to relevant medicinal products towhich paragraph 1 of Schedule 1 to “the 1994 Regulations” apply whichdo not have a UK or EMA authorisation and are commonly known as“specials” (refer to Guidance Note 14), the licence holder shall only importsuch products from another EEA State:

(i) in response to an order which satisfies the requirements of paragraph1 of Schedule 1 to “the 1994 Regulations”; and

(ii) where the following conditions are complied with:

(1) No later than 28 days prior to each importation of an exemptimported product, the licence holder shall give written notice tothe licensing authority stating his intention to import that medicinalproduct and stating the following particulars:(a) the name of the medicinal product, being the brand name or

the common name, or the scientific name, and any name, ifdifferent, under which the medicinal product is to be sold orsupplied in the United Kingdom,

(b) any trademark or name of the manufacturer of the medicinalproduct;

(c) in respect of each active constituent of the medicinal prod-uct, any international non-proprietary name or the Britishapproved name or the monograph name or, where that con-stituent does not have an international non-proprietary name,a British approved name or a monograph name, the acceptedscientific name or any other name descriptive of the true natureof that constituent;

(d) the quantity of medicinal product which is to be imported whichshall not exceed the quantity specified in subparagraph (5);and

(f) the name and address of the manufacturer or assembler of thatmedicinal product in the form in which it is to be importedand, if the person who will supply that medicinal product for


importation is not the manufacturer or assembler, the name andaddress of such supplier.

(2) Subject to subparagraph (3), the licence holder shall not importthe exempt imported product if, before the end of 28 days fromthe date on which the licensing authority sends or gives the licenceholder an acknowledgement in writing by the licensing authoritythat they have received the notice referred to in subparagraph (1)above, the licensing authority have notified him in writing that theproduct should not be imported.

(3) The licence holder may import the exempt imported productreferred to in the notice where he has been notified in writing bythe licensing authority, before the end of the 28 day period referredto in subparagraph (2), that the exempt imported product may beimported.

(4) Where the licence holder sells or supplies exempt imported prod-ucts, he shall, in addition to any other records which he is requiredby the provisions of his licence to make, make and maintain writtenrecords relating to:(i) the batch number of the batch of the product from which the

sale or supply was made; and(ii) details of any adverse reaction to the product so sold or supplied

of which he becomes aware.(5) The licence holder shall import no more on any one occasion than

such amount as is sufficient for 25 single administrations, or for25 courses of treatment where the amount imported is sufficient fora maximum of three months’ treatment, and on any such occasionshall not import more than the quantity notified to the licensingauthority under subparagraph (1)(d).

(6) The licence holder shall inform the licensing authority forthwith ofany matter coming to his attention which might reasonably causethe licensing authority to believe that the medicinal product can nolonger be regarded either as a product which can safely be admin-istered to human beings or as a product which is of satisfactoryquality for such administration.

(7) The licence holder shall not issue any advertisement, catalogue,price list or circular relating to the exempt relevant medicinal prod-uct or make any representations in respect of that product.

(8) The licence holder shall cease importing or supplying an exemptimported product if he has received a notice in writing from thelicensing authority directing that, as from a date specified in thatnotice, a particular product or class of products shall no longer beimported or supplied.

The licence holder shall take all reasonable precautions and exercise alldue diligence to ensure that any information he provides to the licensing


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authority which is relevant to an evaluation of the safety, quality orefficacy of any medicinal product for human use which he handles, storesor distributes is not false or misleading in a material particular.

Appointment and Duties of the Responsible Person

Title VII of the Directive on the Community code relating to medicinalproducts for human use (Directive 2001/83/EC) obliges holders of a dis-tribution authorisation to have a “qualified person designated as responsi-ble”. Regulation 10(1) of the Medicines for Human Use (Manufacturing,Wholesale dealing & Miscellaneous Amendments) Regulations 2005 statethe requirement for a Responsible Person (RP) within the UK. The RP isresponsible for safeguarding product users against potential hazards aris-ing from poor distribution practices as a result, for example, of purchasingsuspect products, poor storage or failure to establish the bona fides ofpurchasers.

The RP should ensure that the conditions of the wholesale dealer’s licence(WL) are met and that the guidelines on Good Distribution Practice (GDP)are complied with. If the RP is not adequately carrying out his duties, thelicensing authority may consider the suspension of the licence, withdrawalof acceptance of the RP on that licence and his acceptability on any otherlicence.

The RP does not have to be an employee of the licence holder but hemust be at his disposal. Where the RP is not an employee there should bea written contract which specifies his responsibilities, duties, authority andso on. In the case of small companies the licensing authority may acceptthe licence holder as the nominated RP. In larger companies, however, thisis not desirable.

There is no statutory requirement for the RP to be a pharmacist, althoughthis is desirable. However, he should have access to pharmaceutical knowl-edge and advice when it is required, and have personal knowledge of:

(a) The relevant provisions of the Medicines Act 1968 as amended andthe Medicines for Human Use (Marketing Authorisations, Etc.) Regu-lations 1994 (SI 1994/3144) as amended.

(b) Directive 2001/83/EC as amended on the wholesale distribution ofmedicinal products for human use.

(c) Guidelines on GDP of medicinal products for human use (94/C 63/03).(d) The conditions of the WL for which he is nominated.(e) The products traded under the licence and the conditions necessary for

their safe storage and distribution.(f) The categories of persons to whom products may be distributed.


Where the RP is not a pharmacist or eligible to act as a Qualified Person(QP) (as defined in Directive 2001/83/EC as amended), he should have atleast one year’s practical experience in both or either of the following areas:

(a) Handling, storage and distribution of medicinal products.(b) Transactions in or selling or procuring medicinal products. In addition,

the RP should have at least one year’s managerial experience in con-trolling and directing the wholesale distribution of medicinal productson a scale, and of a kind, appropriate to the licence for which he isnominated.

To carry out his responsibilities the RP should:

(a) Have a clear reporting line to either the licence holder or the ManagingDirector.

(b) Have access to all areas, sites, stores and records which relate to thelicensable activities being carried out.

(c) Regularly review and monitor all such areas, sites, etc. or have del-egated arrangements whereby he receives written reports that suchactions have been carried out on his behalf. Where arrangements aredelegated, the RP remains responsible and he should personally carryout the delegated functions at least once a year.

(d) Focus on the management of licensable activities, the accuracy andquality of records, compliance with established standard operating pro-cedures, the quality of handling and storage equipment and facilities,and the standards achieved.

(e) Keep appropriate records relating to the discharge of hisresponsibilities.

Where the licence covers a number of sites, the RP may have a nominateddeputy with appropriate reporting and delegating arrangements. However,the RP should assure himself and the licensing authority that the necessarycontrols and checks are in place.

For his part, the licence holder should ensure that there is a writtenstandard operating procedure for receiving advice and comment from theRP and recording the consequent action taken.

Should it prove impossible to resolve a disagreement between the licenceholder and the RP, the licensing authority should be consulted. Whilsta joint referral is clearly to be preferred, either party may approach thelicensing authority independently. If an RP finds that he is in difficulty overhis statutory responsibilities and the activities being carried out under thelicence he should, in strict confidence, consult the licensing authority.


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Control and Monitoring of Storage and Transportation Temperatures

Editor’snote

Legislation and good practices oblige pharmaceutical manufacturers anddistributors to exercise control over the distribution chain to ensure that thequality of medicines is maintained. Critical in this regard is control of theenvironmental conditions under which medicines are stored and transported.The MHRA’s recommendations concerning the control and monitoring ofstorage and transportation temperatures were published in ThePharmaceutical Journal in July 2001.2 A summary of these is given below.

Introduction

1 EU requirements and guidelines on Good Distribution Practice (GDP)require distributors to “ensure that storage conditions are observed at alltimes, including during transportation”. The requirements are applicablenot only to medicines that need to be stored at low temperatures (knownas cold chain products) but also to medicines that should be stored below25◦C or 30◦C (known as temperate chain products). In addition, an increas-ing number of products require storage and transportation at sub-zero tem-peratures and the application of appropriate controls to these is equallyimportant. What follows gives guidance on how compliance with relevantstandards of good practice may be achieved.

Cold storage

2 Many medicinal products require storage at controlled low temperature.Some of these such as vaccines, insulins, blood products and some productsof biotechnology can be denatured by freezing and thus must be maintainedwithin a narrow temperature range above freezing point.

3 The temperature in small refrigerators used to store medicines should bemeasured continuously and the maximum and minimum temperaturesrecorded daily. Sufficient space should be maintained to permit adequateair circulation. If the refrigerator is filled to capacity the effect on temper-ature distribution should be investigated. Refrigerators used for vaccinesand other sensitive products should be capable of maintaining the tempera-ture between 2◦C and 8◦C with the minimum of intervention. Temperature

2 Taylor J. Recommendations on the control and monitoring of storage and trans-portation temperatures of medicinal products. Pharm J 2001; 267: 128–131.


monitoring of these should be by electronic max/min thermometer, withan accuracy of ±0.5◦C, which should be readable from outside the unit.Refrigerators should not be sited in an environment where extremes oftemperature (i.e. < 10◦C or > 32◦C) will affect their performance.

4 Large commercial refrigerators and walk-in cold rooms should be moni-tored with an electronic temperature-recording device that measures loadtemperature in one or more locations, depending on the size of the unit.Portable data-loggers that can be downloaded onto a computer may beused instead of a fixed device. Records should be checked daily. Internal airtemperature distribution should be mapped on installation in the empty andfull state and annually thereafter under conditions of normal use. Productsshould not be stored in areas shown by temperature mapping to presenta risk (e.g. in the airflow from the refrigeration unit). Condensate fromchillers should not be collected inside the unit.

5 Temperature alarms should be fitted to large and walk-in units and thosesmaller units used to store products at risk from freezing.

Controlled room temperature storage

6 The simplest monitoring would be with a max/min thermometer placedat a strategic location and read, recorded and reset at least weekly, morefrequently during periods of exceptionally hot or cold weather. With theexception of very small stores, temperatures should be recorded at lowand high levels. Continuous temperature recording is recommended forlarge warehouses. Self-contained storage areas within warehouses, (e.g.CD store, flammables store) should be included in temperature monitoringprogrammes.

7 All warehouses should be temperature mapped to determine the tempera-ture distribution under extremes of external temperature. Mapping shouldbe repeated every two to three years and after any significant modifica-tion to the premises, stock layout, or heating system. Medicines should notbe stored in areas shown by temperature mapping or other considerationto be unsuitable, e.g. at high level in poorly insulated stores, or next toheaters.

Transportation

COLD-CHAIN GOODS

8 The route and time of transportation, the local seasonal temperatures andthe nature of the load should all be considered when arranging cold-chaindistribution. For small volumes of cold-chain goods, insulated containers


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may be used; in which case it is vital that products damaged by freezingare prevented from coming into direct contact with ice packs at sub-zerotemperatures.

9 Larger volumes of cold-chain goods should be shipped in refrigerated trans-port, particularly if transit times may be prolonged. Temperatures withinloads of products at risk from freezing should be strictly controlled andmonitored with recording probes or individual temperature monitoringdevices, giving consideration to the temperature gradient within the load.The temperature records for each consignment should be reviewed andthere should be a procedure for implementing corrective action in the caseof adverse events.

10 Distributors should ensure that consignments of cold-chain goods areclearly labelled with the required storage/transport conditions. Receiversshould satisfy themselves that the goods have been transported underappropriate conditions and should place them in appropriate storage facil-ities as soon as possible after receipt.

OTHER GOODS

11 Consideration should be given to the possible extremes of temperatureinside uninsulated, unventilated delivery vehicles and precautions shouldbe taken to protect all products from heat challenge. This includes repre-sentatives’ samples kept in car boots and goods distributed using postalservices.

SYSTEMS CHECKS AND CALIBRATION

12 Any systems whose performance is critical to preserving the product shouldbe tested and demonstrated to achieve what is intended. Measuring andrecording devices that are used in critical areas (e.g. temperature moni-toring of storage and transport facilities for cold-chain goods at risk fromfreezing) should be calibrated at least annually against a traceable refer-ence device. Records should include pre- and post-calibration readings anddetails of any adjustments made or corrections to be applied. Alarms shouldbe checked for correct functioning at the designated set temperatures.

Counterfeits/Ensuring Bona Fides

The supply of counterfeit medicines is a growing problem worldwide andone which the MHRA is taking very seriously. Counterfeit medicines rep-resent a threat to the legitimate UK supply chain and to patient safety.They are fraudulent and may be deliberately mislabelled with respectto identity, composition and/or source. Counterfeiting can apply to both


innovator and generic products, prescription and self-medication, as well asto traditional herbal remedies. Counterfeit medicines may include productswith the correct ingredients but fake packaging, with the wrong ingredi-ents, without active ingredients or with insufficient active ingredients, andmay even contain harmful or poisonous substances.

The supply and distribution of medicines is tightly controlled within theEuropean Community. All licensed wholesalers must comply with the Com-munity’s agreed standards of GDP and there exist strict licensing and regu-latory requirements in UK domestic legislation to safeguard patients againstpotential hazards arising from poor distribution practices: for example,purchasing suspect or counterfeit products, failing to establish the “bonafides” of suppliers and purchasers, inadequate record keeping, and so on.

Of principal importance to wholesale dealers is paragraph 31 of the EUGuide to GDP, which states:

“Counterfeit medicinal products found in the distribution network shouldbe kept apart from other medicinal products to avoid any confusion. Theyshould be clearly labelled as not for sale and competent authorities andthe holder of marketing authorisation of the original product should beinformed immediately.”

Manufacturers and wholesale dealers should inform the CompetentAuthority of any defect that could result in a recall or abnormal restrictionon the supply of a product. They must also have effective recall proceduresin place.

Wholesale dealers in particular should maintain a high level of vigilanceagainst the procurement or supply of potentially counterfeit product. Suchproduct may be offered for sale below the established market price sorigorous checks should be made on the bona fides of the supplier and theorigin of the product. It is known that some wholesalers are themselvesdeveloping good practice strategies – such as conducting rigorous physicalinspections of packs when grey market purchases are made – and this isencouraged. Any suspicious activity should be reported to the MHRA’sIntelligence Unit.

The Competent Authority will take regulatory action where breaches oflegislation are identified; this may take the form of adverse licensing actione.g. make a variation to an existing licence, suspension or revocation of alicence and/or the instigation of criminal proceedings.

Diverted Medicines

Diversion is the term used for the fraudulent activity where medicines des-tined for non-EU markets re-enter the EU and are placed back on to theEuropean market at a higher price.


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The diversion of medicines involves medicinal products being offered atpreferential prices and exported to specific markets (normally developingcountries) outside the EU. Diversion occurs when unscrupulous traders, onreceipt of the medicines, re-export the pharmaceutical products back to theEU – meaning that patients for whom these preferentially-priced medicineswere intended are denied access to them. Such products appearing on theEU market are then known as “diverted” from their intended market. Thisrepresents not only a corrupt diversion for profit but such activity alsoposes the risk of inappropriate or unlicensed use, and the quality of theproduct may also be compromised.

As with counterfeit products, wholesale dealers in particular shouldmaintain a high level of vigilance against the procurement or supply ofpotentially diverted product. Such product may be offered for sale belowthe established market value, so appropriate checks should be made on thebona fides of the supplier and the origin of the product.

The Licensing Authority will take regulatory action where breaches oflegislation are identified; this may take the form of adverse licensing actione.g. make a variation to an existing licence, suspension or revocation of alicence and/or the instigation of criminal proceedings.

Parallel Distribution

Parallel distribution embodies two fundamental principles of the Euro-pean Community’s founding Treaty (of Rome): the free movement of goodsand Community-wide exhaustion of intellectual property rights. It is alsoreferred to as parallel trade and also, less correctly (since the EEA3 is asingle market with no internal borders), as parallel importing.

Parallel distribution exists in the absence of price harmonisation of phar-maceutical products within the European Union, i.e. when there are signif-icant price differences between countries; this is the case in the EuropeanUnion, where prices of medicines are not governed by free competitionlaws, but are generally fixed by the government.

It involves the transfer of genuine, original branded products, authorisedin accordance with Community legislation, marketed in one Member Stateof the EEA at a lower price (the source country) to another EEA memberstate (the country of destination) by a parallel distributor, and placed onthe market in competition with a therapeutically identical product alreadymarketed there at a higher price by or under licence from the owner of thebrand.

3 The member states of the European Union plus Iceland, Norway and Liechten-stein.


The pharmaceutical products which are distributed in this way are iden-tical in all respects to the branded version marketed by the originator in thecountry into which it is imported. They are not copies; they do not vary inany respect from the original; and they are manufactured normally by theoriginator or by the licensee to the approved product specification. All suchproducts require a Product Licence for Parallel Import (PLPI) which is a“piggy-back” authorisation granted by the competent regulatory authority(the MHRA in the UK), after extensive checks to ensure that the importeddrug is therapeutically the same as the domestic version.

Parallel distributors operating in the UK are subject to a system of licens-ing and inspection, which ensures that licensed medicinal products conformto internationally agreed standards, and that those medicines are storedand distributed in compliance with the required regulatory standards. Dis-tributors are required to hold a Wholesale Dealer’s Licence, in accordancewith Article 77 of Directive 2001/83/EC, as amended. The only excep-tion is if a manufacturing authorisation includes provision for wholesaledealing. In accordance with the wholesaling authorisation, parallel distrib-utors are obliged to follow GDP guidelines in accordance with Article 84of the Directive, employ a Responsible Person and are subject to periodicinspection by the competent (licensing) authority.

In addition, parallel distributors in the country of destination (the receiv-ing country) involved in repackaging or relabelling of product must employat least one Qualified Person (QP), who has received the relevant educationand training (in accordance with Article 48 of the Directive), with respon-sibility to ensure that a quality system is implemented and maintained. AManufacturing (assembly) Authorisation is also required. Regular GMPinspections are undertaken at parallel assemblers and distributors (per-forming relabelling/repacking activities) by the Competent Authority inthe Member State concerned to ensure that GMP is adhered to.

Parallel distributors are required to have effective recall procedures inplace. The MHRA has systems in place to receive and investigate reports ofpackaging and labelling problems with medicines, including parallel tradedproducts.

Relabelling/repackaging

The goods should remain in their original packaging as long as possible.However, once the received product is approved for processing, relabellingmay be undertaken in accordance with the national simplified marketingauthorisation of the parallel-distributed product, under conditions of GMP,i.e. exactly the same procedures as those followed by all pharmaceuticalmanufacturers.


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This either involves replacement of the original outer carton with a brandnew one or over-stickering the original outer carton, with both providingthe approved label text in the language of the country of destination. Inall cases, the existing package leaflet is removed and replaced by a newone originated by the parallel distributor in accordance with the simplifiedmarketing authorisation in the language of the country of destination. Inaddition to the requirements of the PLPI marketing authorization it maybe necessary, as part of any repackaging specifications, for the applicantto address any trademark concerns that might arise. This may involvetechnical and commercial discussions between the trademark holder andthe PLPI applicant.

Both the original cartons – if these are replaced – and the original leafletsmust be destroyed. No handling of the actual product (e.g. open unitsof tablets or capsules) within its immediate packaging (e.g. blister or foilpacks) should take place during replacement of the original carton and itis important to maintain the audit trail back to the origin.

As with any other pharmaceutical manufacturer, parallel distributoroperators involved in relabelling and/or repackaging should be given reg-ular training in GMP. Batch documentation should be retained for eachbatch.

Maintenance of the integrity of the supply chain

Parallel distributors should only purchase medicinal products with market-ing authorisations from authorised wholesalers or manufacturers in otherEEA countries. The supplying wholesaler should make available before salea copy of its wholesale authorisation and provide assurance that the sup-plies were obtained from the original manufacturer and/or an authorisedwholesaler within the EEA.

Parallel distributors should also only sell or supply medicinal productswith marketing authorisations to authorised wholesalers, registered phar-macies or other persons entitled to sell medicinal products to the generalpublic. A copy of the authorisation should be requested if there is anydoubt.

Continued Supply

Under Article 23a of Directive 2001/83/EC, as inserted by Article 1(22) ofDirective 2004/27/EC, the marketing authorisation holder is required tonotify the Competent Authority (MHRA in the UK) of the date of actualmarketing of the medicinal product, taking account of the various presen-tations authorised, and to notify the Competent Authority if the product


ceases to be placed on the market either temporarily or permanently. Exceptin exceptional circumstances, the notification must be made no less thantwo months before the interruption.

Any authorisation which within three years of granting is not placed onthe market will cease to be valid. In respect of generic medicinal products,the three year period will start on the grant of the authorisation, or at theend of the period of market exclusivity or patent protection of the ref-erence product, whichever is the later date. If a product is placed on themarket after authorisation, but subsequently ceases to be available on themarket in the UK for a period of three consecutive years, it will also ceaseto be valid. In these circumstances the MHRA will, however, when it isaware of the imminent expiry of the three year period, notify the mar-keting authorisation holder in advance that their marketing authorisationwill cease to be valid. In exceptional circumstances, and on public healthgrounds, the MHRA may grant an exemption from the invalidation of themarketing authorisation after three years. Whether there are exceptionalcircumstances and public health grounds for an exemption will be assessedon a case by case basis. When assessing such cases, MHRA will, in particu-lar, consider the implications for patients and public health more generallyof an marketing authorisation no longer being valid.

The MHRA has received requests for advice on implications for main-taining the harmonisation of an authorisation across Member States if apresentation of a product is withdrawn from the market of the ReferenceMember State (RMS) and remains unavailable on that market for threeyears. Discussions on applying the sunset clause provision in such circum-stances continue at EU level. In the meantime the MHRA will address theimplications of this issue on a case by case basis.

Those provisions are implemented in the UK by Regulation 7 of, andSchedule 3 to, the Medicines for Human Use (Marketing AuthorisationsEtc.) Regulations 1994, as amended; in particular, paragraph 6(cc) and 6Bof Schedule 3 each provide that breach of the relevant notification obliga-tion by a UK marketing authorisation holder constitutes a criminal offence.Failure to notify a cessation or interruption, or failure to notify within thetime limit is, however, not an offence if the marketing authorisation holdertook all reasonable precautions and exercised all due diligence to avoidsuch a failure.

In accordance with the MHRA’s interpretation of the expression “plac-ing on the market” when used elsewhere in the Directive, the MHRA’s viewis that a product is “placed on the market” at the first transaction by whichthe product enters the distribution chain in the UK. The marketing au-thorisation holder must, therefore, notify the MHRA when a product witha new marketing authorisation is first placed into the distribution chain,rather than the first date it becomes available to individual patients. TheMHRA requests that you notify us of this first “placing on the market”


I VI V

within one calendar month. In order to ensure that a marketing au-thorisation continues to be valid, the marketing authorisation holder mustensure that at least one packaging presentation (e.g. bottle or blister pack)of the product, which can include own label supplies, authorised underthat marketing authorisation is present on the market.

The marketing authorisation holder must report all cessations/interruptions to the MHRA. However, the MHRA does not need to benotified of the following:

(a) normal seasonal changes in manufacturing and/or distribution sched-ules (such as cold and flu remedies);

(b) short-term temporary interruptions in placing on the market that willnot affect normal availability to distributors.

If you are in doubt about whether or not you need to notify an interrup-tion in supply, you should err on the side of caution and report it to theMHRA in the normal way. You must notify the MHRA if any of the presen-tations authorised under a single marketing authorisation cease to be placedon the market either temporarily or permanently, but, as stated above, theabsence of availability of one or more presentations – as long as one presen-tation of the product authorised under the single marketing authorisationremains on the market – will not invalidate the marketing authorisation.Problems relating to manufacturing or assembly should also be discussedwith the appropriate GMP Inspector and issues of availability of medicinesrelating to suspected or confirmed product defects should be directly noti-fied to, and discussed with, the Defective Medicines Reporting Centre(Tel: 020 7084 2574).

The Department of Health (DH) also has an interest in the availabil-ity of products for supply to the NHS, and together with the Associa-tion of the British Pharmaceutical Industry (ABPI) and the British GenericsManufacturers Association (BGMA), has developed best practice guide-lines for notifying medicine shortages. These guidelines, together withDH/ABPI guidelines “Ensuring Best Practice in the Notification of Prod-uct Discontinuations” complement the statutory requirements under theEuropean legislation and may be found (in PDF format) on the DH web-site (www.dh.gov.uk). Marketing authorisation holders should, therefore,continue to notify the Department of Health about interruptions and ces-sations of marketing in accordance with these guidelines.

In this context, your attention is also drawn to Article 81 of Directive2001/83/EC as substituted by Article 1(57) of Directive 2004/27/EC, underwhich the marketing authorisation holder and the distributors of a medi-cinal product actually placed on the market shall, within the limitsof their responsibilities, ensure appropriate and continued supplies ofthat medicinal product to pharmacies and persons authorised to supply


medicinal products so that the needs of patients in the Member State inquestion are covered. Failure by a marketing authorisation holder to com-ply with this obligation is a criminal offence, unless the marketing authori-sation holder took all reasonable precautions and exercised all due diligenceto avoid such a failure.

Product Recall/Withdrawal

The Medicines Act imposes certain obligations on licence holders withregard to withdrawal and recall from sale. The aim of the DefectiveMedicines Report Centre (DMRC) within the MHRA is to minimise thehazard to patients arising from the distribution of defective (human) medi-cinal products by providing an emergency assessment and communica-tions system between the suppliers (manufacturers and distributors), theregulatory authorities and the end user. The DMRC achieves this by receiv-ing reports of suspected defective (human) medicinal products; monitoringand, as far as is necessary, directing and advising actions by the relevantlicence holder(s) and communicating the details of this action with theappropriate urgency and distribution to users of the products. The com-munication normally used is a “Drug Alert”.

A defective medicinal product is one whose quality does not conform tothe requirements of its marketing authorisation, specification or for someother reason of quality is potentially hazardous. A defective product maybe suspected because of a visible defect or contamination or as a resultof tests performed on it, or because it has caused untoward reactions in apatient or for other reasons involving poor manufacturing or distributionpractice.

An adverse drug reaction means a response to a medicinal product whichis noxious and unintended and which occurs at doses normally used in manfor the prophylaxis, diagnosis or therapy of disease or for the restoration,correction or modification of physiological function.

Counterfeits are considered as defective products.Immediately a hazard is identified from any source, it will be necessary

to evaluate the level of danger, and the category of recall, if required. Wherethe reported defect is a confirmed defect, the DMRC will then take one ofthe following courses of action and obtain a report from the manufactureron the nature of the defect, their handling of the defect and action to betaken to prevent its recurrence.

Issue a “recall’’

Under normal circumstances a recall is always required where a defect isconfirmed unless the defect is shown to be of a trivial nature and/or there


I VI V

are unlikely to be significant amounts of the affected product remaining inthe market.

It is the licence holder’s responsibility to recall products from customers,in a manner agreed with the DMRC. The company should provide copies ofdraft recall letters for agreement with the DMRC. If the company (licenceholder) does not agree to a recall voluntarily, the MHRA, as LicensingAuthority, may be obliged to take compulsory action.

Issue a “Drug Alert’’

Recall and withdrawal of product from the market is normally the respon-sibility of the licence holder. However, where a product has been distributedwidely and/or there is a serious risk to health from the defect, the MHRAcan opt to issue a Drug Alert letter. The Drug Alert cascade mechanismensures rapid communication of safety information; it is not a substitute for,but complimentary to, any action taken by the licence holder. The text of theAlert should be agreed between the MHRA and the company concerned.

In some cases, where a product has been supplied to a small number ofknown customers, the MHRA may decide that notification will be adequateand a Drug Alert is not needed.

The DMRC may also request companies to insert notification in theprofessional press in certain cases.

Management of the recall

The company should directly contact wholesalers, hospitals, retail phar-macies and overseas distributors supplied. The DMRC is likely to take thelead in notifying Regional Contacts for NHS Trusts and Provider Unitsand Health Authorities, special and Government hospitals and overseasregulatory authorities.

The DMRC will liaise with the company and discuss arrangements forthe recall, requesting the dates that supply started and ceased and a copyof any letters sent out by that company concerning the recall. Again, itis desirable that the text of the notices sent via the company and by theDMRC should be mutually agreed.

Follow-up action

The DMRC will monitor the conduct and success of the recall by themanufacturer or distributor. As follow-up action, it may be necessary toconsider any or all of the following:

� arrange a visit to the licence holder/manufacturer/distributor;� arrange a visit to the point of discovery of the defect;� refer to the Inspectorate to arrange an inspection;


� seek special surveillance of adverse reaction reports;� refer the matter for adverse licensing and/or enforcement action.

Reporting a suspected defect

Suspected defects can be reported by telephone, fax, e-mail or letter orusing our online form:

Address:DMRC, Room 17-157, Market Towers, 1 Nine Elms Lane, LondonSW8 5NQ, UK.Telephone: +44 (0)20 7084 2574 (weekdays 0900–1700)Telephone: +44 (0)20 7210 3000 (other times)Fax: +44 (0)20 7084 2676E-mail: [email protected] form: www.mhra.gov.uk

SECTION

V

LEGISLATION ONWHOLESALEDISTRIBUTION

CHAPTER

8

EU Legislation on Wholesale Distribution

Contents

Directive 2001/83/EC, asAmended, Title VII, Wholesaledistribution 371

Directive 2001/83/EC of theEuropean Parliament and of theCouncil of 6 November 2001 onthe Community code relating tomedicinal products for human useas amended by Directive2004/27/EC. 371

Title VII: Wholesale Distribution ofMedicinal Products 372

Article 76 372Article 77 372Article 78 373Article 79 373Article 80 373Article 81 374Article 82 375Article 83 375Article 84 375Article 85 375

DIRECTIVE 2001/83/EC, AS AMENDED, TITLE VII, WHOLESALEDISTRIBUTION

Directive 2001/83/EC of the European Parliament and of the Councilof 6 November 2001 on the Community code relating to medicinalproducts for human use as amended by Directive2004/27/EC.

Editor’snote

Title VII of this directive is reproduced below. Reference should be made tothe full Directive for the preamble, definitions and the general and finalprovisions.

371

372 V LEGISLATION ON WHOLESALE DISTRIBUTION

Title VII: Wholesale Distribution of Medicinal Products

Article 76

1 Without prejudice to Article 6, Member States shall take all appropriateaction to ensure that only medicinal products in respect of which a mar-keting authorization has been granted in accordance with Community laware distributed on their territory.

2 In the case of wholesale distribution and storage, medicinal products shallbe covered by a marketing authorisation granted pursuant to Regulation(EC) No. 726/2004 or by the competent authorities of a Member State inaccordance with this Directive.

3 Any distributor, not being the marketing authorisation holder, who importsa product from another Member State, shall notify the marketing author-isation holder and the competent authority in the Member State to whichthe product will be imported of his intention to import it. In the caseof products which have not been granted an authorisation pursuant toRegulation (EC) No. 726/2004, the notification to the competent authorityshall be without prejudice to additional procedures provided for in thelegislation of that Member State.

Article 77

1 Member States shall take all appropriate measures to ensure that the whole-sale distribution of medicinal products is subject to the possession of anauthorization to engage in activity as a wholesaler in medicinal products,stating the place for which it is valid.

2 Where persons authorized or entitled to supply medicinal products to thepublic may also, under national law, engage in wholesale business, suchpersons shall be subject to the authorization provided for in paragraph 1.

3 Possession of a manufacturing authorization shall include authorization todistribute by wholesale the medicinal products covered by that authoriza-tion. Possession of an authorization to engage in activity as a wholesalerin medicinal products shall not give dispensation from the obligation topossess a manufacturing authorization and to comply with the conditionsset out in that respect, even where the manufacturing or import businessis secondary.

4 At the request of the Commission or any Member State, Member Statesshall supply all appropriate information concerning the individual author-izations which they have granted under paragraph 1.

5 Checks on the persons authorized to engage in the activity of wholesalerin medicinal products and the inspection of their premises shall be carried


VV

out under the responsibility of the Member State which granted the autho-rization.

6 The Member State which granted the authorization referred to in para-graph 1 shall suspend or revoke that authorization if the conditions ofauthorization cease to be met. It shall forthwith inform the other MemberStates and the Commission thereof.

7 Should a Member State consider that, in respect of a person holding anauthorization granted by another Member State under the terms of para-graph 1, the conditions of authorization are not, or are no longer met,it shall forthwith inform the Commission and the other Member Stateinvolved. The latter shall take the measures necessary and shall inform theCommission and the first Member State of the decisions taken and thereasons for those decisions.

Article 78

Member States shall ensure that the time taken for the procedure for exam-ining the application for the distribution authorization does not exceed 90days from the day on which the competent authority of the Member Stateconcerned receives the application.

The competent authority may, if need be, require the applicant to sup-ply all necessary information concerning the conditions of authorization.Where the authority exercises this option, the period laid down in the firstparagraph shall be suspended until the requisite additional data have beensupplied.

Article 79

In order to obtain the distribution authorization, applicants must fulfil thefollowing minimum requirements:

(a) they must have suitable and adequate premises, installations and equip-ment, so as to ensure proper conservation and distribution of the medi-cinal products;

(b) they must have staff, and in particular, a qualified person designatedas responsible, meeting the conditions provided for by the legislationof the Member State concerned;

(c) they must undertake to fulfil the obligations incumbent on them underthe terms of Article 80.

Article 80

Holders of the distribution authorization must fulfil the following mini-mum requirements:


(a) they must make the premises, installations and equipment referred toin Article 79(a) accessible at all times to the persons responsible forinspecting them;

(b) they must obtain their supplies of medicinal products only from personswho are themselves in possession of the distribution authorization orwho are exempt from obtaining such authorization under the terms ofArticle 77(3);

(c) they must supply medicinal products only to persons who are them-selves in possession of the distribution authorization or who are au-thorized or entitled to supply medicinal products to the public in theMember State concerned;

(d) they must have an emergency plan which ensures effective implemen-tation of any recall from the market ordered by the competent author-ities or carried out in cooperation with the manufacturer or marketingauthorization holder for the medicinal product concerned;

(e) they must keep records either in the form of purchase/sales invoices,or on computer, or in any other form, giving for any transactionin medicinal products received or dispatched at least the followinginformation:� date,� name of the medicinal product,� quantity received or supplied,� name and address of the supplier or consignee, as appropriate;

(f) they must keep the records referred to under (e) available to the com-petent authorities, for inspection purposes, for a period of five years;

(g) they must comply with the principles and guidelines of good distribu-tion practice for medicinal products as laid down in Article 84.

Article 81

With regard to the supply of medicinal products to pharmacists and personsauthorised or entitled to supply medicinal products to the public, Mem-ber States shall not impose upon the holder of a distribution authorisationwhich has been granted by another Member State any obligation, in par-ticular public service obligations, more stringent than those they imposeon persons whom they have themselves authorised to engage in equivalentactivities.

The holder of a marketing authorisation for a medicinal product and thedistributors of the said medicinal product actually placed on the marketin a Member State shall, within the limits of their responsibilities, ensureappropriate and continued supplies of that medicinal product to pharma-cies and persons authorised to supply medicinal products so that the needsof patients in the Member State in question are covered.


VV

The arrangements for implementing this Article should, moreover, bejustified on grounds of public health protection and be proportionatein relation to the objective of such protection, in compliance with theTreaty rules, particularly those concerning the free movement of goods andcompetition.

Article 82

For all supplies of medicinal products to a person authorized or entitled tosupply medicinal products to the public in the Member State concerned,the authorized wholesaler must enclose a document that makes it possibleto ascertain:

� the date;� the name and pharmaceutical form of the medicinal product;� the quantity supplied;� the name and address of the supplier and consignor.

Member States shall take all appropriate measures to ensure that personsauthorized or entitled to supply medicinal products to the public are ableto provide information that makes it possible to trace the distribution pathof every medicinal product.

Article 83

The provisions of this Title shall not prevent the application of more strin-gent requirements laid down by Member States in respect of the wholesaledistribution of:

� narcotic or psychotropic substances within their territory;� medicinal products derived from blood;� immunological medicinal products;� radiopharmaceuticals.

Article 84

The Commission shall publish guidelines on good distribution practice. Tothis end, it shall consult the Committee for Medicinal Products for HumanUse and the Pharmaceutical Committee established by Council Decision75/320/EEC.

Article 85

This Title shall apply to homeopathic medicinal products.

CHAPTER

9

UK Legislation on Wholesale Distribution

Contents

The Medicines for Human Use(Manufacturing, WholesaleDealing and MiscellaneousAmendments) Regulations2005 (SI 2005 No. 2789) 377

Interpretation 377Requirement that holders of

wholesale dealer’s licencescomply with certainobligations 378

Requirement that wholesaledealers deal only with specifiedpersons 380

Requirement as to responsiblepersons 381

Standard provisions for wholesaledealer’s licences 382

Schedule 4: Standard ProvisionsWhich May be Incorporated in aWholesale Dealer’s Licence 382

The Medicines for Human Use (Manufacturing, Wholesale Dealingand Miscellaneous Amendments) Regulations 2005 (SI 2005No. 2789)

Editor’snote

These extracts from the Regulations and Standard Provisions of TheMedicines for Human Use (Manufacturing, Wholesale Dealing andMiscellaneous Amendments) Regulations 2005 [SI 2005 No. 2789] arepresented for the reader’s convenience. Reproduction is with the permissionof HMSO and the Queen’s Printer for Scotland. For any definitive informationreference must be made to the original Regulations. The numbering andcontent within this section corresponds with the regulations set out in thepublished Statutory Instrument (SI 2005 No. 2789).

Interpretation

1 (1) These Regulations may be cited as The Medicines for Human Use(Manufacturing, Wholesale Dealing and Miscellaneous Amendments)Regulations 2005.

377


(2) In these Regulations:“the Act” means the Medicines Act 1968;“the 1994 Regulations” means the Medicines for Human Use (Mar-keting Authorisations Etc.) Regulations 1994;“the Applications Regulations” means the Medicines (Applications forManufacturer’s and Wholesale Dealer’s Licences) Regulations 1971;“the Standard Provisions Regulations” means the Medicines (StandardProvisions for Licences and Certificates) Regulations 1971;“the Directive” means Directive 2001/83/EC, of the European Parlia-ment and of the Council on the Community code relating to medicinalproducts for human use, as amended by:(a) Directive 2002/98/EC of the European Parliament and of the Coun-

cil of 27 January 2003 setting standards of quality and safety for thecollection, testing, processing, storage and distribution of humanblood and blood components,

(b) Commission Directive 2003/63/EC amending Directive2001/83/EC on the Community code relating to medicinalproducts for human use,

(c) Directive 2004/24/EC of the European Parliament and of theCouncil amending, as regards traditional herbal medicinal prod-ucts, Directive 2001/83/EC on the Community code relating tomedicinal products for human use, and

(d) Directive 2004/27/EC of the European Parliament and of the Coun-cil amending Directive 2001/83/EC on the Community code relat-ing to medicinal products for human use;

“EEA State” means a Member State, Norway, Iceland or Liechtenstein;“exempt relevant medicinal product” means a relevant medicinal prod-uct to which paragraph 1 of Schedule 1 to the 1994 Regulations or anyequivalent legislation in any EEA State other than the United Kingdomapplies;“the guidelines on good distribution practice” means the Guidelineson Good Distribution Practice of Medicinal Products for Human Use(94/C63/03) published by the European Commission pursuant to Arti-cle 84 of the Directive;“relevant medicinal product” means a medicinal product for humanuse to which the provisions of the Directive apply;

(3) Expression used in these Regulations which are used in any provisionof the Act have the meaning which they bear in the Act.

Requirement that holders of wholesale dealer’s licences comply withcertain obligations

8 (1) The holder of a wholesale dealer’s licence, insofar as that licence relatesto relevant medicinal products, shall:


VV

(a) comply with the guidelines on good distribution practice;(b) ensure, within the limits of his responsibility as a distributor of rel-

evant medicinal products, the appropriate and continued supply ofsuch relevant medicinal products to pharmacies and persons whomay lawfully sell such products by retail or who may lawfully sup-ply them in circumstances corresponding to retail sale so that theneeds of patients in the United Kingdom are covered;

(c) provide and maintain such staff, premises, equipment and facilitiesfor the handling, storage and distribution of the relevant medicinalproducts which he handles, stores or distributes under his licenceas are necessary to maintain the quality of, and ensure proper dis-tribution of, the medicinal products which he handles, stores ordistributes pursuant to his licence;

(d) inform the licensing authority of any proposed structural alterationto, or discontinuance of use of, premises to which the licence relatesor premises which have been approved from time to time by thelicensing authority.

(2) Subject to paragraph (3), the holder of a wholesale dealer’s licence shallnot sell or offer for sale or supply any relevant medicinal product unless:(a) there is a marketing authorization for the time being in force in

respect of that product; and(b) the sale or offer for sale is in conformity with the provisions of that

authorisation.(3) The restriction in paragraph (2) shall not apply to:

(a) the sale or offer for sale of any exempt relevant medicinal product;and

(b) the export to an EEA State, or supply for the purposes of suchexport, of a relevant medicinal product which may be placed on themarket in that State without a marketing authorization by virtue oflegislation adopted by that State under Article 5(2) of the Directive.

(4) The holder of a wholesale dealer’s licence shall:(a) keep such documents relating to the sale of medicinal products

to which his licence relates as will facilitate the withdrawal orrecall from sale of relevant medicinal products in accordance withparagraph (b);

(b) have in place an emergency plan which will ensure effective imple-mentation of the recall from the market of any relevant medicinalproducts where such recall is:(i) ordered by the licensing authority or by the competent authority

of any other EEA State; or(ii) carried out in co-operation with the manufacturer of, or the

holder of the marketing authorization for, the product inquestion;

(c) keep such records, which may be in the form of purchase and salesinvoices, or on a computer or in any other form, which give, as a


minimum, where any relevant medicinal products are received ordispatched, the following information:(i) the date of receipt or, as the case may be, dispatch,

(ii) the name of the relevant medicinal product,(iii) the quantity of relevant medicinal product received or, as the

case may be, dispatched, and(iv) the name and address of, as may be applicable in each case, the

person from whom the products are received or to whom theyare sold or supplied.

(5) Where the holder of a wholesale dealer’s licence imports from anotherEEA State any relevant medicinal product in respect of which he is noteither:(a) the marketing authorization holder in respect of that product; or(b) acting on behalf of the marketing authorization holder in importing

that product, he shall notify the marketing authorization holder andthe licensing authority of his intention to import it.

(6) The licence holder, for the purpose of enabling the licensing authorityto ascertain whether there are any grounds:(a) for suspending, revoking or varying any licence granted under Part

II of the Act; or(b) suspending or terminating any licence in accordance with the

provisions of Part II of the Act, shall permit, and provide allnecessary facilities to enable, any person duly authorised in writingby the licensing authority, on production if required of his creden-tials, to carry out such inspection or to take such samples or copies,in relation to things belonging to, or any business carried on by, theholder of the licence, as such person would have the right to carryout or take under the Act for the purpose of verifying any statementcontained in an application for a licence.

Requirement that wholesale dealers deal only with specified persons

9 (1) The holder of a wholesale dealer’s licence shall obtain supplies of rele-vant medicinal products only from either:(a) a manufacturer’s licence holder or wholesale dealer’s licence holder

in respect of such products; or(b) a person who holds an authorisation granted by another EEA State

authorizing the manufacture of such products or their distributionby way of wholesale dealing.

(2) The holder of a wholesale dealer’s licence shall distribute relevantmedicinal products by way of wholesale dealing only to:(a) a holder of a wholesale dealer’s licence relating to those products;


VV

(b) a holder of an authorization granted by the competent authority ofanother EEA State authorising the supply of those products by wayof wholesale dealing;

(c) any person who may lawfully sell those products by retail or whomay lawfully supply them in circumstances corresponding to retailsale; or

(d) any person who may lawfully administer those products.(3) Where any relevant medicinal product is supplied to any person pur-

suant to paragraph (2)(c), the licence holder shall enclose with theproduct a document which makes it possible to ascertain:(a) the date on which the supply took place;(b) the name and pharmaceutical form of the product supplied;(c) the quantity of product supplied; and(d) the names and addresses of the person or persons from whom the

products were supplied to the licence holder.(4) The licence holder shall:

(a) keep a record of the information supplied pursuant to paragraph(3) for a minimum period of five years after the date on which it issupplied; and

(b) ensure, during that period, that that record is available to the licens-ing authority for inspection.

Requirement as to responsible persons

10 (1) Where a wholesale dealer’s licence relates to relevant medicinal prod-ucts, the wholesale dealer’s licence holder shall at all times haveat his disposal the services of a person (referred to in this regula-tion as “a responsible person”) who, in the opinion of the licensingauthority:(a) has knowledge of the activities to be carried out and of the pro-

cedures to be performed under the licence which is adequate forperforming the functions of responsible person; and

(b) has experience in those procedures and activities which is adequatefor those purposes.

(2) The functions of the responsible person shall be to ensure, in relationto relevant medicinal products, that:(a) the conditions under which the licence has been granted have been,

and are being, complied with; and(b) the quality of relevant medicinal products which are being handled

by the wholesale dealer’s licence holder are being maintained inaccordance with the requirements of the marketing authorizationsapplicable to those products.


(3) The licence holder shall:(a) notify the licensing authority of the name and address and degrees,

diplomas or qualifications and experience of the person who willcarry out the functions of responsible person;

(b) notify the licensing authority of any change to the responsible per-son; and

(c) not permit any person to act as responsible person other than theperson named in his licence as responsible person or, subject toparagraph (4) any other such person whose name is notified to thelicensing authority.

(4) Where, after giving the licence holder and the person acting as a respon-sible person the opportunity of making representations to them (orallyor in writing), the licensing authority are of the opinion that:(a) the person so acting does not satisfy the provisions of paragraph

(1) as respects qualifications and experience, or(b) he is failing to carry out the duties referred to in paragraph (2)

adequately or at all, and have notified the licence holder accordinglyin writing, the licence holder shall not permit that person to act asa responsible person.

Standard provisions for wholesale dealer’s licences

11 The standard provisions, for the purposes of Part II of the Act, for wholesaledealer’s licences, insofar as those licences relate to relevant medicinal prod-ucts, shall be those provisions set out in Schedule 4 to these Regulations.

Schedule 4 Standard Provisions Which May be Incorporated in aWholesale Dealer’s Licence

1 The licence holder shall not use any premises for the purpose of the han-dling, storage or distribution of relevant medicinal products other thanthose specified in his licence or notified to the licensing authority by himfrom time to time and approved by the licensing authority.

2 The licence holder shall provide such information as may be requested bythe licensing authority concerning the type and quantity of any medicinalproducts which he handles, stores or distributes.

3 (1) Where and insofar as the licence relates to relevant medicinal productsto which paragraph 1 of Schedule 1 to the 1994 Regulations apply,the licence holder shall only import such products from another EEAState:(a) in response to an order which satisfies the requirements of para-

graph 1 of Schedule 1 to the 1994 Regulations; and


VV

(b) where the conditions set out in sub-paragraphs (2) to (9) are com-plied with.

(2) No later than 28 days prior to each importation of an exemptimported product, the licence holder shall give written notice to thelicensing authority stating his intention to import that medicinal prod-uct and stating the following particulars:(a) the name of the medicinal product, being the brand name or the

common name, or the scientific name, and any name, if different,under which the medicinal product is to be sold or supplied in theUnited Kingdom;

(b) any trademark or name of the manufacturer of the medicinalproduct;

(c) in respect of each active constituent of the medicinal product, anyinternational non-proprietary name or the British approved nameor the monograph name or, where that constituent does not havean international non-proprietary name, a British approved nameor a monograph name, the accepted scientific name or any othername descriptive of the true nature of that constituent;

(d) the quantity of medicinal product which is to be imported whichshall not exceed the quantity specified in sub-paragraph (6); and

(e) the name and address of the manufacturer or assembler of thatmedicinal product in the form in which it is to be imported and, ifthe person who will supply that medicinal product for importationis not the manufacturer or assembler, the name and address of suchsupplier.

(3) Subject to sub-paragraph (4), the licence holder shall not import theexempt imported product if, before the end of 28 days from the dateon which the licensing authority sends or gives the licence holder anacknowledgement in writing by the licensing authority that they havereceived the notice referred to in sub-paragraph (2) above, the licens-ing authority have notified him in writing that the product should notbe imported.

(4) The licence holder may import the exempt imported product referredto in the notice where he has been notified in writing by the licensingauthority, before the end of the 28-day period referred to in sub-paragraph (3), that the exempt imported product may be imported.

(5) Where the licence holder sells or supplies exempt imported products,he shall, in addition to any other records which he is required by theprovisions of his licence to make, make and maintain written recordsrelating to:(a) the batch number of the batch of the product from which the sale

or supply was made; and(b) details of any adverse reaction to the product so sold or supplied

of which he becomes aware.


(6) The licence holder shall import no more on any one occasion thansuch amount as is sufficient for 25 single administrations, or for 25courses of treatment where the amount imported is sufficient for amaximum of three months’ treatment, and on any such occasion shallnot import more than the quantity notified to the licensing authorityunder sub-paragraph (2)(d).

(7) The licence holder shall inform the licensing authority forthwith ofany matter coming to his attention which might reasonably cause thelicensing authority to believe that the medicinal product can no longerbe regarded either as a product which can safely be administered tohuman beings or as a product which is of satisfactory quality for suchadministration.

(8) The licence holder shall not issue any advertisement, catalogue, pricelist or circular relating to the exempt relevant medicinal product ormake any representations in respect of that product.

(9) The licence holder shall cease importing or supplying an exemptimported product if he has received a notice in writing from the licens-ing authority directing that, as from a date specified in that notice, aparticular product or class of products shall no longer be imported orsupplied.

(10) In this paragraph:� “British approved name” means the name which appears in the cur-

rent edition of the list prepared by the appropriate body in accor-dance with Section 100 of the Act and published by the Ministerson the recommendation of the Commission and “current” in thisdefinition means current at the time the notice is sent to the licensingauthority;

� “common name” means the international non-proprietary nameor, if one does not exist, the usual common name;

� “international non-proprietary name” means a name which hasbeen selected by the World Health Organization as a recom-mended international non-proprietary name and in respect of whichthe Director-General of the World Health Organization has givennotice to that effect in the World Health Organization Chronicle;and

� “monograph name” means the name or approved synonymwhich appears at the head of a monograph in the current edi-tion of the British Pharmacopoeia, the British PharmaceuticalCodex, the European Pharmacopoeia or a foreign or interna-tional compendium of standards and “current” in this defini-tion means current at the time the notice is sent to the licensingauthority.


VV

4 The licence holder shall take all reasonable precautions and exercise alldue diligence to ensure that any information he provides to the licens-ing authority which is relevant to an evaluation of the safety, quality orefficacy of any medicinal product for human use which he handles, storesor distributes is not false or misleading in a material particular.

SECTION

VI

GLOSSARY OFLEGISLATION

Glossary of Legislation

Contents

European Legislation 389Primary (UK) Legislation 389

Secondary Legislation (UK StatutoryInstruments) 390

European Legislation

Council Directive 2001/83/EC on the Community code relating to medicinalproducts for human use as amended by Directive 2004/27/EC and Directive2004/24/EC and Directive 2002/98/EC

This legislation regulates the licensing, manufacture of and wholesale deal-ing in medicinal products within the European Community.

Council Directive 2003/94/EC laying down the principles and guidelines of goodmanufacturing practice in respect of medicinal products for human use andinvestigational medicinal products

This Directive lays down the principles and guidelines of good manufac-turing practice in respect of medicinal products for human use whose man-ufacture requires an authorisation.

Primary (UK) Legislation

Medicines Act 1968 as amendedThis Act regulates, in part, the manufacture, distribution and importationof medicinal products.

389

390 GLOSSARY OF LEGISLATION

Secondary Legislation (UK Statutory Instruments)

The Medicines for Human Use (Manufacturing, Wholesale Dealing andMiscellaneous Amendments) Regulations 2005 (SI 2005 No. 2789)

Replaces, as respects medicinal products to which the relevant EU legisla-tion applies (“relevant medicinal products”), the existing regulations whichimplement the Directive 2001/83/EC, as amended. Sets out the obligationswith which holders of manufacturer’s and wholesale dealer’s licenses mustcomply in respect of those licences.

The Medicines (Applications for Manufacturer’s and Wholesale Dealer’s Licences)Regulations 1971 (SI 1971 No. 974), as amended

These Regulations relates to applications for the grant of manufacturer’sand wholesale dealer’s licences other than licences of right. They prescribethe form and manner in which such applications are to be made, and specifythe information that shall accompany each application.

Medicines (Manufacturer’s Undertakings for Imported Products) Regulations1977 (SI 1977 No. 1038), as amended

These Regulations relate to prescribed conditions for manufacturer’s under-takings for imported products.

Medicines for Human Use (Marketing Authorisations Etc.) Regulations 1994 (SI1994 No. 3144), as amended

Provide the functions for the Competent Authority of a member State underthe relevant Community provisions Directive 2001/83/EC as amended by2004/27/EC are, except as otherwise provided, to be performed in the UKby the Licensing Authority. They also provide that no medicinal productfor human use which is subject to the relevant Community provisions maybe placed on the market or distributed in the UK other than in accordancewith a current marketing authorisation granted by the Licensing Authorityor the European Commission.

The Medicines (Products for Human Use – Fees) Regulations 1995 (SI 1995No. 1116), as amended

These Regulations make provision for the fees payable under the MedicinesAct 1971 in respect of marketing authorizations, licences and certificatesrelating to medicinal products for human use.

The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004No. 1031) as amended

These Regulations implement Directive 2001/20/EC on the approximationof laws, regulations and administrative provisions of the Member Statesrelating to the implementation of good clinical practice in the conduct ofclinical trials on medicinal products for human use.

Glossary of legislation 391

The Unlicensed Medicinal Products for Human Use (Transmissible SponigformEncephalopathies) (Safety) Regulations 2003 (SI 2003 No. 1680)

Regulates the importation and marketing of unlicensed medicinal prod-ucts for human use in order to minimise the risk of the transmission ofTransmissible Spongiform Encephalopathies via those products.

Prescription Only Medicines (Human Use) Order 1997 (as amended) (SI 1997No. 1830), as amended

This order specifies the descriptions and classes of prescription onlymedicines.

SECTION

VII

INDEX

Index

A

acceptance criteria, definition 264Active Pharmaceutical Ingredient (API) 219

in clinical trials see under Clinical trialsdefinition and synonym 217, 219, 264herbs, GMP for 293ICH, guidelines 41low molecular weight 258medicinal gases 129short shelf-lives 246starting material, definition 217, 265sterile products, water quality for 225see also Active substance starting materials

Active Pharmaceutical Ingredient (API)manufacturing

agents, brokers, traders, distributors, repackersand relabellers 256

handling of complaints and recalls 257handling of returns 258quality management 256stability studies 257traceability of distributed APIs 256transfer of information 257

audits of manufacturers 294buildings and facilities 223

containment 225defined areas/control systems 224design and construction 223lighting 226sanitation and maintenance 226sewage and refuse 226utilities 224water supplies 225

cell culture/fermentation used in see Cell culture;Fermentation

change control 252APIs for use in clinical trials 264

clinical trial use 262see also Clinical trials

complaints and recalls 254, 257contract manufacturers/laboratories 255Directive 2001/83/EC 302documentation and records 229

APIs for use in clinical trials 264batch control records 232batch production record review 234batch production records 232, 234duration of retention 230electronic signatures 230equipment cleaning and use record 230format for retention 230indelible recording 230labelling and packaging materials 231laboratory control records 233, 234master control records 231master production instructions 231raw materials, intermediates (records) 231retention procedures 230systems and specifications for 229validated analytical methods 251

glossary 264GMP for, requirements 293laboratory controls 243

APIs for use in clinical trials 264Certificates of Analysis 245expiry and retest dating 246general controls 243impurity profile 244, 249, 253out-of-specification results 243reagents and reference solutions 243reference standards 244reserve/retention samples 246specifications 243stability monitoring 245testing of intermediates and APIs 244

materials management 234APIs for use in clinical trials 263bulk deliveries 235critical materials 234

395

396 INDEX

Active Pharmaceutical Ingredient (API) (cont.)general controls 234identification of materials 235preprocessing/reworking 237re-evaluation of materials 236receipt and quarantine 235rejected materials 236sampling/testing of incoming materials 235storage of materials 236suppliers 235

packaging and identification labelling 240checking 242facilities for 241general requirements 240label issuance and control 240label requirements/information included 241packaging materials 240procedures 241sealing of containers 242

personnel 222consultants 223hygiene 222qualifications 222training 222

principles and guidelines of GMP 303process equipment 226, 237

calibration 228cleaning, documentation 230computerised systems 228dedicated, records 231design and construction 226maintenance and cleaning 227for use in clinical trials 263

production and in-process controls 237APIs for use in clinical trials 263blending batches 239contamination control 239expiry dates of batches 239in-process sampling and controls 238personnel for in-process controls 238production operations 237raw material handling 237time limits 237written procedures 238yields (actual vs expected) 237

quality management 219agents, brokers, traders, distributors, repackers

and relabellers 256internal audits (self inspection) 221principles 219product quality review 222

quality units and responsibilities of 219, 220responsibility for production activities 221for use in clinical trials 262

rejection and re-use of materials 252recovery of materials/solvents 254rejection 252reprocessing 253returns 254reworking of batches 253

storage and distribution 242distribution procedures 242warehousing procedures 242

validation 247analytical methods 251APIs for use in clinical trials 263cleaning 250critical parameters/attributes for 247, 249documentation 247equipment cleaning 251periodic review 250policy 247process validation approaches 248process validation program 249, 263qualification 248

Active Pharmaceutical Ingredient (API) startingmaterial, definition 217, 265

active substance starting materialsdefinition 217, 265guidelines and directives 216

Directive 2001/83/EC 302scope of guidelines 216

introduction into process 217manufacturing stages 217, 219objectives of guidelines 216production

initiation 217see also Active Pharmaceutical Ingredient (API)

manufacturingsterile products 216synonym (API) 219see also Active Pharmaceutical Ingredient (API)

active substances, definition and synonym 217,219

adverse drug reaction, definition 366aerosol formation

biological medicinal products 108immunological veterinary product manufacture

120, 124aerosol preparations, manufacture, pressurised

metered doses 144filling 144, 145

INDEX 397

general 144leakage tests 145one-shot process (cold filling) 144premises and equipment 144principle 144production and Quality Control 144two-shot system (pressure filling) 144, 145

aflatoxins 138agents (brokers), APIs 256air

laminar air flow see Laminar air flow systemsfrom radiopharmaceutical manufacturing areas

111recirculation control, cross-contamination

prevention 68ventilation of immunological veterinary product

premises 117air filtration

API manufacturing facilities 224biological medicinal product manufacture 106sterile product manufacture 93see also HEPA filter

air-flow patterns, clean rooms 93air pressure

immunological veterinary product manufacture118

manufacture of radiopharmaceuticals 110medicinal gas cylinders 131

air separation plant, definition 134air shower 90air supply

API manufacture 224biological medicinal product manufacture

106immunological veterinary product manufacture

117radiopharmaceutical manufacture 110sterile product manufacture 93warning system for failures 94

airborne particulates, classification 87airlocks

definition 207immunological veterinary product manufacture

118sterile product manufacture 86, 93

analytical methodsvalidation 76see also Testing (analysis)

ancillary areas 56animal feedingstuffs, medicated, manufacture of

premixes 112

animal houses 121biological product manufacture 106conditions/requirements 119design and siting 121immunological veterinary product manufacture

121manufacturers’ obligations 275prescribed conditions for manufacturer’s

undertakings for imported products 336siting 56

animal tissue material, personnel involved 91animals 121

biological product manufacture 106care, biological product manufacture 106contact, standard provisions for manufacturer’s

licence relating to vaccines 329health status 107identification system 121immunological veterinary product manufacture

121killing, smallpox vaccine manufacturer’s licence

331on-going stability testing 78sanitary status 121standard provisions for manufacturer’s licence

relating to sera 333standard provisions for manufacturer’s licence

relating to vaccines 330BCG vaccine 332

for testing of materials/products 77antibiotics, ionophore, in horses 113antisera, manufacturer’s licences, standard provisions

for 322, 333apheresis systems, inspection 175API see Active Pharmaceutical Ingredient (API)area, manufacturing, medicinal gases, definition 134aseptic preparation 90

clean rooms/areas 87sampling 88see also Sterile medicinal products, manufacture

aseptic processingvalidation 95

investigational medicinal product 162see also Clean areas

aseptic productsfreeze-drying 91handling 91

Association of the British Pharmaceutical Industry(ABPI), notification of interruptions in supply365

“audit trail” 147

398 INDEX

auditsindependent, after self inspection 85internal, API manufacturing 221

autoclave, barrier double-door 118

B

Bacillus anthracis 105backing-up of electronic data 148batch(es) 188

blending, API manufacturing 239bulk production see Bulk production batchcertification by QP see Batch release, and

certification for (by QP)checking after product defect complaint 83definition 207, 265

for continuous processes (medicinal gases) 130documentation

Directive 2003/94/EC 310see also Batch records

finished product see Finished product batchimmunological veterinary product manufacture

124medicinal gases 130number for on-going stability testing 78numbers

definition 207, 265packaging 71

process simulation test, validation of asepticprocessing 95

production records, API manufacturing 232,234

review 234prospective process validation 182

sale of batches 182recovery 72register, maintenance by QP 281release see Batch releaseretrospective validation 183sizes, radiopharmaceuticals 110starting materials 69testing

location of sampling 193products imported from country with mutual

recognition agreement 194products imported from third country 192, 193products manufactured in EC/EEA 190

batch records 58API manufacturing 232electronic storage 59in GMP 45

immunological veterinary products 124investigational medicinal products 161irradiated products 155medicinal gasespackaging records 62processing records 62production records, API manufacturing 232,

234Quality Control requirements 75sterile medicinal products 97, 100

batch release, and certification for (by QP) 187bulk production batch 190

with different marketing authorisations191

with single marketing authorisation 190computerised system 148, 189confirmation by other QPs 188, 189

agreement for 189content for products exported to countries under

MRA 291criteria, Marketing Authorisation 187EC/EEA manufacturing site(s) 189

different sites 190single site 190

EU Directives 187Directive 2001/83/EC 306

imported from country with mutual recognitionagreement 194

legal requirements 281investigational medicinal products 166,

167manufacture and imported from third country 187,

188, 192complete batch imported 192part of finished product batch imported 193reference samples 204testing of samples 192testing of samples, EC/EEA sites 193

medicinal gases 133principle 187process and quality system needed 188products manufactured in EC/EEA 190professional misconduct on 282purchased by manufacturing authorisation holder

191quality control laboratory/production site under

different marketing authorisations 192rationale 188reason for control of 188reference and retention samples 202

responsibility for taking/storing 203

INDEX 399

regulations/requirementsroutine duties of QP 280see also Code of Practice for Qualified Persons

requirements 188, 280stages contracted out 190see also Parametric release

BCG vaccine 104, 105standard provisions in manufacturer’s licence 331

beta radiation see Electron irradiationbioburden 96, 259

definition 265biofermenters 105biogenerators 119, 124

definition 207biological agents

containment see Containmentcontamination/infection of personnel 116contamination outside premises 116definition 207inactivated, handling 117live, handling during production 117production 118storage, equipment for 120

biological indicatorsheat sterilisation monitoring 98radiation sterilisation 99sterilisation monitoring 97sterilisation with ethylene oxide 100

biological medicinal products, manufacture 103animal quarters and care 106from blood/plasma products see Blood and plasma

productscontamination and cross-contamination 105control, biological analytical techniques 104documentation 107investigational medicinal products 162personnel 104premises and equipment 105principle 103production 107

operating principles 108seed lot and cell bank system 107starting materials 107

quality control 109retention samples 109scope, types of manufacturing process 103specifications 107training for 104

biological processes, involved in manufacture ofbiological products 103

“biotechnological process” 258

blending, definition in API manufacturing 239“blinded” products 162blinding

definition 157, 307investigational medicinal products 162

blood, definition 173blood and plasma products 172

collection of blood/plasma 174contract with manufacturer 174premises 174see also Blood donation

CPMP guidelines 173definition 173disposal of rejected products 178documentation 174, 175EU Directives 172homogeneous plasma pool, testing 176infection transmission 172

post collection information on 175preventive measures 172

labels on plasma for pooling/fractionation 177look-back procedures 176, 177manufacturer’s licence holder obligations 319manufacturers’ obligations 272monitoring of quality 174plasma fractionation

contamination prevention 177labels for 177

premises and equipment 174principle 172production and quality control 176quality, factors affecting 172Quality Assurance criteria 173Quality Management 173retention of samples 177return of products 174screening for infective agents 172storage 176testing before release 176, 177traceability and post collection measures 175

information required 175viral inactivation/removal 174

identification of products 177withdrawal of batch 176

blood bags, inspection 175blood components, definition 173blood donation 174

confidentiality issues 175disinfection of donor skin 175identification of donors 175premises 174

400 INDEX

blood transfusioncomponents for 173infections after 176

blow/fill/seal technology 90blowing down, definition 134Borderline Products, Guidance Notes 7British approved names 327, 328, 384British Generics Manufacturers Association (BGMA),

notification of interruptions in supply 365British Pharmacopoeia, MHRA role in managing

4British Pharmacopoeia Commission 4brokers, APIs 256buildings

API manufacturing 223see also Active Pharmaceutical Ingredient (API)

manufacturingsee also Premises

bulk gas, definition 134bulk production

batch release and certification 190medicinal gases 129

bulk production batch 190definition 195release see Batch release, and certification for

(by QP)bulk products

definition 208medicinal gases 129, 130, 132processing operations 70receipt, handling on 66specifications 60stability 77

C

calibrationdefinition 208, 265process equipment, API manufacturing

228weighing/measuring equipment 57

campaign working 54biological medicinal products 105immunological veterinary products 115veterinary medicinal products 113

carryover of materials, contamination in APImanufacturing 239

“caution in use” alert 6ceilings, false 93cell bank

definition 208

maintenance and record keeping 260master 208working 208

cell bank system 107biological product manufacture 107contamination 108

prevention 108testing and characterisation 123

definition 208establishment 123generation number between finished product and

107, 122immunological veterinary product manufacture

122personnel handling 108, 123stability and storage 108storage 123

cell cultureAPIs manufactured by 258

biological processes involved 259contamination 260equipment and environmental controls

259harvesting, isolation and purification 261personnel for 260procedures and media 260process controls 259virus removal/inactivation 261

definition 208CEN/ISO standards, manufacture of medicinal

products 42centrifugation

biological medicinal products 108immunological veterinary product manufacture

123cephalosporins, containment, in API manufacturing

225Certificate of Analysis 235, 245

authorisation 245competency of organisation issuing 292components/requirements 292information included 245UK guidance 292

certificationfinished product batch, definition 195by Qualified Person see Batch release, and

certification for (by QP); Qualified Person(s)change control

API manufacturing 252, 264definition 185procedures 184, 252

INDEX 401

sterile products 198validation 184

changing rooms 56immunological veterinary product manufacture

118sterile product manufacture 92, 93

chemical indicators, heat sterilisation monitoring98

chromatography 109“classical fermentation” 258clean areas

activities in, minimised and controlled 96blood and plasma products 177classification for sterile product manufacture 86clothing for 92contamination prevention 92definition 208disinfectants and detergents for 94equipment 94fumigation 95immunological veterinary products 117microbiological monitoring 88personnel in 91for plasma fractionation 177precautions for personnel 91, 92premises 92sanitation 94sterile medicinal product manufacture 87sterilisation of equipment 96temperature and humidity 96transfer operations 96, 124validation of new procedures 96, 97

clean/contained areadefinition 208see also Clean areas; Contained area

“clean in place” systems 106cleaning

clean areas 94clothing for clean areas 92containers/valves, for aerosol production 145cross-contamination prevention 68equipment 56

for API manufacturing 227design 56documentation, API manufacturing 230validation, API manufacturing 251

incubators 125pipework, medicinal gases 131production areas, biological medicinal product

manufacture 106records 230

cleaning validation 183analytical methods for 183API manufacturing 250definition 185intervals between use and 183number of cleaning applications 184rationale for, and limits of 183representative range and “worst case” approach

184“test until clean” 184

clinical trialsAPIs for use in 262

change control 264control of raw materials 263documentation 264equipment and facilities 263laboratory controls 264production 263quality 262validation 263

definition 157emergency unblinding 164labelling of investigational medicinal products

163, 165Marketing Authorisation for product use

277products for see Investigational medicinal

productsproducts supplied to participants 156regulation, MHRA role 4responsibilities of Qualified Person(s) 277see also Comparator product; Investigational

medicinal productsclosed systems 105, 124, 142Clostridium botulinum 105Clostridium tetani 105clothing 92

animal quarter work 107API manufacturing 222aseptic production 90changing rooms/facilities 56for clean areas 92outdoor, sterile product manufacture 92for personnel 92protective, for personnel 51

API manufacturing 222cross-contamination prevention 68

sterile product manufacture 92by Grade 92

Co-rapporteur 4Code of Ethics, of RPSGB 288

402 INDEX

Code of Practice for Qualified Persons (UK) 276application 278continuing professional development 285contract manufacturing/testing 284Contracted Qualified Person(s) 283disciplinary procedures 287general principles 279legal framework (EU Directives) 279number and location of QPs 283performance of duties and regulatory compliance

282professional conduct 286purpose 277regulatory basis 277routine duties of QPs 280terminology 278

cold-chain goods, transportation 358cold storage 357Commission on Human Medicines 4commissioning of plant, ionising radiation, use in

manufacture 151recommissioning 153

Committee for Proprietary Medicinal Products(CPMP) 103

blood and plasma products 173“common name” 384common names (drugs) 328comparator product

definition 157expiry dates 162modified 162principles applicable to 162

complaints on products 83advising authorities 84APIs 254

handling by agents/brokers/traders257

batch checking after 83counterfeiting 83decisions, recording 83Directive 2003/94/EC 313GMP requirement 45investigational medicinal products 169principle 83product defects, investigation 83records 83responsible persons 83system, prescribed conditions for manufacturer’s

undertakings for imported products 337written procedures 83

compressed gas, definition 134

computer systemsdefinition 265medicinal gas manufacture 130

computerised systems 146, 228breakdown

alternatives 148API manufacturing 229

changes, records of and authorisation 229checking system 147data entry, personnel for 147data security and protection 147definition 209, 265documentation 146equipment for API manufacturing 228incidents related to API manufacturing 229manual system in parallel 147operator identity and authorisation 147outside agencies supplying services 148personnel 146, 147principle 146requirements/features 146security and restricted access, API manufacturing

229software 147

API manufacturing 229validation 146

concurrent validation 182API manufacturing 248definition 185

confidentiality issues, blood donors 175confirmation, by QP, definition 196consultants, Active Pharmaceutical Ingredients (API)

223contained area

definition 209live biological agent handling 116, 117transfer operations 124

containersAPI manufacturing 240blow/fill/seal technology 90bulk, starting materials 69cleaning, for aerosol production 145closure, sterile products 101damaged 66definition 134filling instructions 71immediate, investigational medicinal products

164immunological veterinary product manufacture

125irradiation 154, 155

INDEX 403

medicinal gases 128, 131, 134filling and labelling 130, 132see also Cylinders

parenteral products, inspection 101pressurised metered dose aerosol preparations 145for samples 76starting materials 69sterile medicinal products 101storage, API materials 235veterinary medicinal products 113see also Cryogenic vessels; Packaging

containmentAPI manufacturing 225biological agents, equipment for 120definition 208premises, immunological veterinary product

manufacture 117primary 208

of biological organisms 106, 116secondary 209

contaminantshazardous 67seed lots and cell banks 108

contaminationcell culture and fermentation 260control/minimisation

API manufacturing 224, 239sterile product manufacture 86

definition 265high-risk, terminally sterilised products 90injectable products 67investigational medicinal products 159liquids, creams and ointments 142outside premises, with biological agents 116personnel, immunological veterinary products 116premises for biological product manufacture 105pressurised metered dose aerosol preparations 145seed lots and cell banks see Cell bank system; Seed

lotssources, isolator technology and 89starting materials 67see also Cross-contamination

continued supply 363continuing professional development (CPD) 287

Qualified Persons 285records 285UK statements 287

Institute of Biology 287Royal Pharmaceutical Society of Great Britain

288Royal Society of Chemistry 289

continuous culture 109immunological veterinary product manufacture

126contract manufacture and analysis 80

API manufacturing 255computerised service 148Contract Acceptor 80, 81

inspection 82requirements of 81requirements of Contract Giver towards 80responsibilities 81third party involvement 81, 255

Contract Giver 80provisions to Contract Acceptor 80responsibilities 80right to visit premises 82

contracts 81, 255for analysis of samples 81documentation 82Qualified Person role 81requirements/information included 81responsibilities outlined 81

Directive 2003/94/EC 312finished product batch release 190general issues 80ionising radiation use 149laboratories 75principle 80Qualified Person’s responsibilities 284records 82testing (analysis) 81written contract and inclusions 80

contract manufacturers 266APIs 255subcontractors 81, 255

Contracted Qualified Person(s) 283Code of Practice information for CEO 284duties 284

controlled area, definition 209controlled room temperature storage 358conveyor belt, sterile product manufacture 94cooling, sterile 98counterfeit medicinal products

definition 366Good Distribution Practice (GDP) guidelines

346types 359UK guidance 359wholesalers’ obligations 360

counterfeiting 359complaint on product 83

404 INDEX

creams see Liquids, creams and ointmentsCreutzfeldt-Jakob disease (CJD) 175,

296critical process, definition 266cross-contamination

biological medicinal products 105definition 209, 266personnel, immunological veterinary products

116prevention in production 53, 67

biological products 68checking 68containment, in API manufacturing

225immunological veterinary products

116veterinary medicinal products 112, 113see also Contamination

crude plant 209cryogenic gas

definition 134filling of vessels 133

cryogenic vesselsdefinition 133, 134, 209filling 133

culturecell see Cell culturecontinuous see Continuous culturemicrobial 103

culture media 108, 260immunological veterinary product manufacture

122sterilisation 109see also Cell culture

cylinder bundle, definition 134cylinders

definition 134, 209empty, segregation 127filling 132

mixture of gases 132preparation for 132uninterrupted operation cycle 132

filling pressures 131labelling 130medicinal gases 131

refilling 131“test code date” 131

protection from adverse weather 133purging 135storage and release 133testing 132

D

datacomputerised see Computerised systemselectronic, backing-up 148entry into computer, personnel for 147for retrospective validation 183security and protection 147storage, Directive 2003/94/EC 310see also Documentation

decontaminationeffluents containing micro-organisms 106equipment, immunological veterinary product

manufacture 120immunological veterinary product manufacture

123personnel

for biological product manufacture 104immunological veterinary products 116

procedures 68dedicated facilities

APIs 223biological medicinal products 105blood and plasma products 174immunological veterinary products 118radiopharmaceuticals 110

defective medicinal productsdefinition 366reporting, contact details 368

Defective Medicines Report Centre (DMRC) 6, 366,367

follow-up after recall 367management of recall 367

deliveriesinvestigational medicinal products 168receipt for 63

deliveries to customers, Good Distribution Practice(GDP) guidelines 345

Department of Health, notification of interruptions insupply 365

designbuildings/facilities, API manufacturing 223documentation 58equipment 56

for appropriate cleaning 56immunological veterinary product manufacture

120gamma irradiators 151isolator technology 89process equipment, for API manufacturing

226

INDEX 405

production areas 54biological medicinal product manufacture 106

Quality Control Laboratories 56design qualification (DQ) 180

API manufacturing 248definition 185

destruction of productsinvestigational medicinal products 169rejected blood/plasma products 178returned products 73see also Disposal of products

detergents, for clean areas, monitoring 94deviation, definition 266Devices Evaluation Service, MHRA role in managing

4disciplinary procedures, Qualified Person(s) 287discontinued products, notification 365disinfectants, for clean areas, monitoring 94disinfection

effluents, immunological veterinary products 118,121

skin, blood donors 175disposal of products

broken seals on products 344immunological veterinary products 121, 124manufacturers’ obligations 273rejected blood/plasma products 178see also Destruction of products

distributionActive Pharmaceutical Ingredients (API) 242to customers, Good Distribution Practice (GDP)

guidelines 345investigational medicinal products 168manufacturers’ obligations 272, 273radiopharmaceuticals 111receipt of products, Good Distribution Practice

(GDP) guidelines 344see also Wholesale distribution

distribution recordsradiopharmaceuticals 111required for product recall 84

distributorsAPIs 256quality system 342see also Wholesalers

diversion, definition 360diverted medicines 360documentation 58

alterations and signing of 59API manufacturing see Active Pharmaceutical

Ingredient (API) manufacturing

approval and signing-off 58batch packaging records 62batch processing records 62batches, Directive 2003/94/EC 310biological medicinal product manufacture 107blood and plasma products 174, 175bulk production of medicinal gases 129clarity of documents 58complaints on products 83computerised systems 146contract manufacture and analysis 82design and review 58Directive 2003/94/EC 310documents required 59electronic/photographic, Directive 2003/94/EC

310electronic/photographic, authorisations 59EU legislation for wholesale distribution 375general requirements 58Good Distribution Practice (GDP) guidelines

343handwritten, limiting and clarity 59herbal medicinal product manufacture 137

processing instructions 138specifications for starting materials 137

immediate completion 59immunological veterinary product manufacture

119, 124accumulation prevention 124

investigational medicinal products seeInvestigational medicinal products(manufacture of)

ionising radiation use in manufacture 155laboratory, Quality Control 75manufacturer’s licence 326manufacturing formulae 60medicinal gases, manufacture 128packaging instructions 61principles 58procedures 63processing instructions 60, 61qualification 179Quality Control 75radiation treatment 155recording of testing results 76records 63

see also Recordsretention 59, 75specifications 58, 59unambiguous contents 58up-to-date 58

406 INDEX

documentation (cont.)validation 179

APIs 247wholesale dealer’s licence obligations 379wholesale dealer’s obligations 350

doors, clean areas 93dose mapping 150

electron irradiation 153gamma irradiators 152

dosimeterscalibration 150causes of inaccuracy 150dose mapping of electron irradiators 153dose mapping of gamma irradiators 152reference 152

dosimetry 150radiation sterilisation 99

drainsAPI manufacturing 225in production areas 54

“Drug Alert” 6, 366classification 6issuing 367

drug products see Medicinal productsdrug substance

definition 266see also Active Pharmaceutical Ingredient (API)

dry heat sterilisation 99dust

accumulation prevention in clean areas 93generation, precautions 54generation, production of premixes 112precautions for handling 67

E

eating and drinking, by personnel 51restrictions, API manufacturing 223

ectoparasiticides, manufacture 113, 217effluents

containing micro-organisms, decontamination 106disinfection, immunological veterinary products

118, 121electron irradiation 149

commissioning 153design of irradiators 153dose mapping 153processing 155

electronic databacking-up 148see also Computerised systems

electronic documentation, Directive 2003/94/EC 310emergency deliveries, by wholesalers 345emergency plan for recalls 346

wholesale dealer’s licence 379wholesale dealer’s obligations 350

emergency unblinding 164Directive 2003/94/EC 313

emulsions, preparation 90, 91endotoxins 96, 99, 259Enforcement and Intelligence Group 7

objectives and duties 7enforcement officers 7environmental controls, API manufacturing, by cell

culture or fermentation 259equipment 53, 56

API manufacturing 223, 226by cell culture or fermentation 259for use in clinical trials 263see also Active Pharmaceutical Ingredient (API)

manufacturingbalances and measuring 57biological product manufacture 105blood and plasma products 174calibration, API manufacturing 228cell culture 260for chromatography 109clean areas 94cleaning/washing 56

API manufacturing 227validation, API manufacturing 251

defective, removal 57design 56

for appropriate cleaning 56immunological veterinary product manufacture

120Directive 2003/94/EC 310Good Distribution Practice (GDP) guidelines 344for handling live organisms 106immunological veterinary product manufacture

118, 119, 124installation 56investigational medicinal product manufacture

159laboratory, testing, Quality Control 77liquids, creams and ointments manufacture 142log books 65maintenance/cleaning, API manufacturing 227manufacturer’s licence holder obligations 317manufacturers’ obligations 272manufacturing, design and location 56medicinal gases, manufacture 127

INDEX 407

for on-going stability testing 78operating procedures, records 65prescribed conditions for manufacturer’s

undertakings for imported products 335pressurised metered dose aerosol preparation 144principles 53production, hazard prevention to products 56qualification and 181radiopharmaceuticals, manufacture 110repair and maintenance 56requirements 56sensitive, in Quality Control Laboratories 56sterile medicinal product manufacture 94

maintenance 94validation 94

sterilisation 94, 96immunological veterinary products 120

storage of biological agents 120validation 181warning/alarms 120

ethylene oxide, sterilisation 100cycle, monitoring 100records 100requirements 100

EURATOM Directives 110European Economic Area (EEA) 187

batch release sites 189European Union

Directive 91/256/EEC, repeal 314Directive 92/25/EEC 342Directive 2001/83/EC 389

manufacturing 299, 365wholesale distribution 371

Directive 2003/94/EC 306, 389addressees 314complaints, product recall and emergency

unblinding 313compliance with marketing authorisation 308conformity with GMP 308definitions 307documentation 310entry into force, date 314inspections 307labelling 314personnel 309premises and equipment 310production 311quality assurance system 309quality control 311scope 307self-inspection 313

transposition 314work contracted out 312

Directivesactive substance starting materials 216batch release 187blood and plasma products 172investigational medicinal productsQualified Person certification 187regulatory basis for Qualified Persons 277

Guidance on wholesale distribution practice seeGood Distribution Practice (GDP), EUguidelines

legislation 389see also Legislation

pharmaceutical industry 40wholesale distribution legislation 371

see also Wholesale distributionevacuation, of gas, definition 134exotic organisms, definition 209expiry (expiration) dates

APIs 246comparator products 162definition 266printing after packaging 71

export certificates 6export of products, wholesale dealer’s obligations

350eye-sight tests, inspectors 101

F

facilitiesAPI manufacturing 223

for use in clinical trials 263dedicated see Dedicated facilitiesmanufacturer’s licence holder obligations 317prescribed conditions for manufacturer’s

undertakings for imported products 335validation 181see also Premises

feedingstuffs, medicated, manufacture of premixes112

fermentationAPIs manufactured by 258

biological processes involved 259classical fermentation 258contamination 260equipment and environmental controls 259harvesting, isolation and purification 261personnel for 260procedures and media 260

408 INDEX

fermentation (cont.)process controls 259recombinant DNA technology 258virus removal/inactivation 261

classical 258principles 258

fermenters 108, 124filling/filling processes

aerosol preparations, manufacture 144containers 71cryogenic vessels 133cylinders see Cylindersimmunological veterinary products 125liquids, creams and ointments 142medicinal gases 132sterilised products 90, 96

filtersin-line sterilising, for biological products 109integrity, assessment 101pore sizes 100requirements 101

filtration of air see Air filtrationfiltration of products

in-line sterilising, for biological products 109infusion fluids 96not sterilised in final container 100pressurised metered dose aerosol preparations 145second filtration process 101

finished product batchcertification 189

definition 195definition 196quality control, Directive 2003/94/EC 312records of distribution 64release see Batch release, and certification for

(by QP)finished products 72

certification 189definition 195see also Batch release

definition 210generation number between seed lot or cell bank

and 107liquid, cream and ointment production 143parametric release see Parametric releaseQuality Control assessment 74quarantine 72reference samples see Reference samplesrelease 72

see also Batch release, and certification for(by QP)

retention of samples see Retention samplesspecifications 60sterile products 101storage 72testing after reprocessing 72

finishing of sterile products 101“first in first out” principle 344fraudulent activity

diverted medicines 360see also Counterfeit medicinal products

freeze dryers, loading/unloading, immunologicalveterinary products 121

freeze-drying, aseptic products 91fumigation, clean areas 95

G

gamma irradiation 149batch mode 149, 154commissioning 151continuous mode 149, 154design of irradiators 151dose mapping 152processing 154

garments see Clothinggas(es)

definition 135liquefied, definition 135liquifiable, definition 210medicinal see Medicinal gases

gas cylinders see Cylindersglass apparatus, liquids, creams and ointments

manufacture 142glossaries 38, 134, 157, 173, 185, 195, 199,

207API manufacturing 264on legislation 389

gloves, sterile product manufacture 92Good Clinical Practice (GCP), MHRA Inspectors’

role 5Good Distribution Practice (GDP) 341

MHRA Inspectors’ role 5Good Distribution Practice (GDP), EU guidelines

341counterfeit products 346deliveries to customers 345documentation 343

orders 343procedures 343records 343

emergency plan and recalls 346

INDEX 409

personnel 342premises and equipment 344

receipt of goods 344storage of products 344

principle 341provision of information to member states

347returns 345

non-defective medicinal products 345products classified as not for sale 347

self-inspection 347storage and temperature conditions 357

Good Laboratory Practice (GLP)MHRA Inspectors’ role 5Quality Assurance scope 43Quality Control 75

Good Manufacturing Practice (GMP) 9, 44active substances 216definition (EC Directive) 307description and requirements 44Directive 2003/94/EC

conformity with GMP 308see also European Union

EU directives 41MHRA Inspectors’ role 4as part of Quality Assurance 44principles and application of 41

Directive 2003/94/EC 306Quality Assurance scope 43Quality Control as part 45

“Good Manufacturing Practices” 279Good Pharmacovigilance Practice (GpvP), MHRA

Inspectors’ role 5GPRD (General Practice Research Database), MHRA

role in managing 4Grades, for sterile product manufacture see Sterile

medicinal products, manufactureGuidance Notes, from MHRA 7Guide to Good Manufacturing Practice 41

H

hair, sterile product manufacture, precautions92

hand-washing 52harmonisation of authorisations 364harvesting, APIs produced by cell

culture/fermentation 261head of Production Department 48, 49

duties and responsibilities 49shared with head of Quality Control 50

head of Quality Control 48, 49responsibilities 49

shared with head of Production Department 50headgear, sterile product manufacture 92heat sterilisation 97, 98

media, immunological veterinary productmanufacture 122

moist 98starting materials, immunological veterinary

product manufacture 122HEPA filter 110

dry heat sterilisation 99immunological veterinary product manufacture

117see also Air filtration

hepatitis C virus (HCV) 176, 177hepatitis viruses 175, 176, 177

testing for 176herbal medicinal products

APIs, GMP for 293definition 210

herbal medicinal products, manufacture 137documentation 137

processing instructions 138specifications for starting materials 137

premises 137principle 137production areas 137Quality Control 139sampling 138storage areas 137

herbicides, containment, in API manufacturing 225high-energy electron irradiation see Electron

irradiationHIV 1 and 2 175, 176

antibodies 176testing for 176

homeopathic products, wholesale distribution, EUlegislation 375

“Human Plasma for Fractionation” label 177humidity

clean areas 96premises 53

hydrostatic pressure test, definition 135hygiene

personal 91of personnel 51, 91

API manufacturing 222Directive 2003/94/EC 309

programmes 51hypersensitivity, penicillins 113

410 INDEX

I

identification system, animals 121ill-health, personnel, API manufacturing cautions 223immediate packaging

definition 158investigational medicinal products 164

immunological status, personnel, for biologicalproduct manufacture 104

immunological veterinary products, manufacture 115animals and animal houses 121disinfection and waste disposal 121documentation 119equipment 119inactivation 125personnel 115premises 116principle 115production 122Quality Control 126retention samples 126starting materials see Starting materialsvariability and inefficiency 115variety and volume 115

importation, Directive 2001/83/EC 299imported products

certification by QP 192, 281, 290, 306country with mutual recognition agreement 194The Medicines for Human Use (Manufacturing,

Wholesale Dealing and MiscellaneousAmendments) Regulations 2005 319, 326

standard provisions 326prescribed conditions for manufacturer’s

undertakings 335“specials” 294unlicensed medical products 294

for individual patients 295wholesale, EU legislation 372wholesale dealer’s licence 380wholesale dealer’s obligations 351

importers 192batch testing and release of products see Batch

release, and certification for (by QP)definition 196notifications of intention to import 295, 327

contact details 296impurity, definition 266impurity profile

APIs 244, 249reworked 253

definition 266

in-process control(s)API manufacturing 237

see also Active Pharmaceutical Ingredient (API)manufacturing

biological medicinal products 109definition 210, 266immunological veterinary product manufacture

126investigational medicinal products 161medicinal gas manufacture 130for testing 77

in-process sampling, API manufacturing 238inactivated biological agents, handling 117incubators

cleaning/disinfection 125immunological veterinary product manufacture

120infected, definition 210infectious disease

personnel 51API manufacturing cautions 223

post-transfusion 176transmission by blood and plasma products 172

post collection information on 175preventive measures 172testing for 176, 177

see also Virusesinfusion fluids, filtration 96inhalation, pressurised aerosol preparations for see

Aerosol preparations, manufactureinjectable products, contamination 67injections, water for 94insects

prevention in manufacture of herbal products137

prevention in manufacture of premixes 112inspection

Directive 2003/94/EC 307by licensing authority, manufacturers’ obligations

272, 274parenteral products 101self- see Self inspection

Inspection and Standards Division, of MHRA 4Inspectorate Group, of MHRA 4inspectors, working relationship with Qualified

Person(s) 286installation qualification (IQ) 180


Institute of Biology, CPD statement 287Intelligence Unit, of MHRA 7

INDEX 411

intermediate productsAPI manufacturing

cell culture and fermentation 258distribution and transport 242process equipment for 226records of 231repacking and relabelling 256returns 254testing 244traceability after distribution 256see also Active Pharmaceutical Ingredient (API)

manufacturingbatch testing and release in EC/EEA 190biological medicinal products 109definition 210, 266immunological veterinary product manufacture

126processing operations 70specifications 60

International Conference on Harmonisation (ICH )41

international non-proprietary name 328, 384interruptions in supply, reporting 365investigational medicinal products (manufacture of)

156batch documentation 310batch release 166

assessment for certification before 167manufactured at different sites 168packaging/labelling at investigator site 168

blinding operations 162comparator products see Comparator productcomplaints 169

Directive 2003/94/EC 313complexity 156definition 157, 307destruction 169documentation 159

manufacturing formulae and processinginstructions 160

order 160packaging instructions 161processing, testing and packaging batch records

161product specification file 160specifications and instructions 159

emergency unblinding, Directive 2003/94/EC 313EU Directive 2001/20/EC 168

imported product 166product sourced in EU 166

GMP application 156

guidelines 156manufacturer/importer 158order 160packaging 163packaging materials 161personnel 156, 159premises and equipment 159principle 156product return/re-labelling 168product specification file 166production 161

blinding operations 162labelling 163manufacturing operations 161principles applicable to comparator product

162randomisation code 163

Qualified Person(s), duties 168Quality Control 165quality management 158recalls 169reconciliation of delivered/used and recovered

products 169return of products 169samples for quality control 166shipping 168sponsors 167, 168, 169toxicity, potency and sensitising potential 159traceability 159, 160, 170transfers between sites 168two-step release procedure 168use-by date 165

Investigational Medicinal Products Authorisation279

investigators, definition 158ionising radiation, use in manufacture 149

commissioning of plant 151documentation 155dosimetry 150electron irradiation see Electron irradiationgamma irradiation see Gamma irradiationinterruptions and phasing 154microbiological monitoring 155monitoring of radiation dose 154premises 153principle 149processing 154responsibilities 149segregation of non-irradiated products 154specification requirements 150validation 150, 155

412 INDEX

irradiation see Ionising radiation, use in manufacture;Radiation

isolator technology 89contamination sources 89monitoring 89utilisation and designs 89validation 89

isotopes, half-lives 110

J

jewellery, wearing 92

K

key personnel 48

L

labellingafter packaging 71APIs 240

label issuance and control 240records 231for use in clinical trials 262see also Active Pharmaceutical Ingredient (API)

manufacturingblood and plasma products 177Directive 2003/94/EC 314dispensed starting materials 69investigational medicinal products 163

at investigator site 168requirements 163use-by date 165

of materials during processing 67medicinal gases & cylinders 130pipework, labelling of contents 57plasma for pooling/fractionation 177printing after packaging 71relabelling see Relabellingsample containers 76starting materials 69stored starting materials 69

labelscut and roll-feed 71storage of printed materials 70

laboratoriescontract 75, 255

see also Contract manufacture and analysiscontrols, API manufacturing see Active

Pharmaceutical Ingredient (API)manufacturing

Good Practice see Good Laboratory Practice (GLP)testing of reagents and equipment 77

laboratory areas, API manufacturing 224laboratory control records, API manufacturing 233,

234laboratory documentation

notebooks/records, retention 75Quality Control 75

laboratory reagentsstorage 77testing 77testing and preparation dates, Quality Control

77laminar air flow systems 87

immunological veterinary product manufacture119

starting materials for 124radiopharmaceuticals manufacture 110

laundry facilities 92leak tests

autoclaves 98gas cylinders 133isolators 89pressurised aerosol products 145

legislationEuropean Union 389glossary 389on manufacture 300

EU see European Union (individual Directives)UK, The Medicines for Human Use

(Manufacturing, Wholesale Dealing andMiscellaneous Amendments) Regulations2005 316

UK 389on wholesale distribution

EU 371UK 377see also Wholesale distribution

see also The Medicines for Human Use(Manufacturing, Wholesale Dealing andMiscellaneous Amendments) Regulations2005

licensing authorityinformation for, by manufacturer 272, 274, 275,

318on imported products 328

Qualified Person assessment 275, 276licensing of medicines, MHRA role in authorising 4Licensing Office

of MHRA Inspection and Standards Division 5staff responsibilities 6

INDEX 413

lightingAPI manufacturing 226of premises 53production areas 55

liquefied gas, definition 135liquids, creams and ointments 142

premises and equipment 142principle 142production 142storage 142, 143

liquifiable gas, definition 210log books 65lot(s) see Batch(es)lot number see Batch(es), numberslubricants, for equipment, API manufacturing 227

M

maintenancecell bank 260equipment 56

API manufacturing 227premises 53workshops 56

make-up, in clean areas 92manifold(s)

definition 135, 210for medicinal gases 128, 131, 132, 135

manufacture (of medicinal products)biological see Biological medicinal products,

manufactureCEN/ISO standards and 42contract see Contract manufacture and analysisdefinition 210, 267Directive 2001/83/EC 299herbal products see Herbal medicinal products,

manufactureimmunological veterinary products see

Immunological veterinary products,manufacture

investigational products see Investigationalmedicinal products (manufacture of)

ionising radiation use see Ionising radiation, use inmanufacture

legislation see Legislation, on manufactureprocesses, described in GMP 44radiopharmaceuticals see Radiopharmaceuticals,

manufacture“specials” 294sterile products see Sterile medicinal products,

manufacture

UK guidancemanufacturers’ obligations 272Qualified Persons see Qualified Person(s)

see also specific types of products andmanufacturing stages

manufacturersdefinition 210, 307obligations, UK guidance 272

Qualified Persons 275responsibility, for marketing authorisations 80undertakings for imported products see Imported

productsmanufacturer’s licence 275

documentation 326Guidance Notes 7holders, obligations 317legislation see The Medicines for Human Use

(Manufacturing, Wholesale Dealing andMiscellaneous Amendments) Regulations 2005

obligations under 274prescribed conditions for manufacturer’s

undertakings for imported products 337Standard Provisions 273, 323Standard Provisions (Schedule 1 of Regulations)

323Standard Provisions for imported products

(Schedule 2 of Regulations) 326manufacturing

formulae, documentation 58safety of personnel 42

Manufacturing Authorisation 43, 279, 290contents 283Directive 2001/83/EC 300EU legislation on wholesale distribution 372issue of by competent authority 301legal responsibilities 43obligations of holder 302requirements 300

information needed 300, 302for QPs 303

time for granting 301manufacturing formulae, documentation 60

investigational medicinal products 160manufacturing sites

overseas, GMP Inspectors’ role 5see also Premises

Marketing Authorisation 40, 43, 277, 279batch release criteria 187compliance with conditions by QP 283date of product in distribution chain 364date of product on market 363

414 INDEX

Marketing Authorisation (cont.)Directive 2003/94/EC, compliance 308expiry 364harmonisation across EU 364products not on market 364requirements for 42responsibilities of manufacturers 80supply failures 364

master production instructions, API manufacturing231

materialsdefinition 267management in API manufacturing see Active

Pharmaceutical Ingredient (API)manufacturing

recovery, API manufacturing 254starting see Starting materials

maximum theoretical residual impurity, definition135

mediacell culture and fermentation 108, 260immunological veterinary product manufacture

122sterilisation 109see also Cell culture

Medical Devices Agency 3medical examination, at recruitment 51medicated feedingstuff 112medicinal gases 135

cryogenic 133cylinders see Cylindersdefinition 135deliveries 130glossary terms 134liquefied, definition 135liquifiable, definition 210manufacture see Medicinal gases, manufacturemixed, in cylinders 132testing 132

medicinal gases, manufacturecylinders see Cylindersdocumentation 128personnel 127premises and equipment 127principle 127production see Productionpurification 129Quality Control 132retention samples 133specifications 130, 132storage and release 133

medicinal plants see Plants, medicinalmedicinal products

definition 210, 266, 307derived from human blood/plasma see Blood and

plasma productsdiscontinuations, notification 365for individual patients see “Specials”

Medicines, Ethics and Practice; A Guide forPharmacists 288

Medicines Act 1068 389Medicines and Healthcare products Regulatory

Agency (MHRA)advice and guidance issued 7advisory bodies 4contact details 8Enforcement and Intelligence Group 7formation 3Inspection and Standards Division 4Inspectorate 4Licensing Office 5new medicine application assessment 3objectives and responsibilities 3reporting of cessations/interruptions in supply

365reporting when product in distribution 364roles 3

Medicines Control Agency 3Medicines for Human Use (Marketing Authorisations

etc.) Regulations 1994 390The Medicines for Human Use (Clinical Trials)

Regulations 2004 390The Medicines for Human Use (Manufacturing,

Wholesale Dealing and MiscellaneousAmendments) Regulations 2005 5, 316, 390

interpretation 316, 377manufacturer’s licence holder obligations 317

for import of medicinal products 319offence relating to sale/supply of starting materials

322qualified persons, requirements 320Schedule 1 (manufacture/assembly of medicinal

products) 323Schedule 2 (import of medicinal products) 326Schedule 3 (standard provisions relating to

vaccines) 329Schedule 4 standard provisions incorporated into

wholesale dealer’s licence 382standard provisions relating to vaccines, toxins and

sera 322, 329BCG vaccines 331sera 333

INDEX 415

smallpox vaccines 330toxins 333

wholesale distribution 377see also Wholesale distribution

The Medicines (Applications for Manufacturer’s andWholesale Dealer’s Licences) Regulations1091 390

Medicines (Manufacturer’s Undertakings forImported Products) Regulations 1977 390

The Medicines (Products for Human Use – Fees)Regulations 1995 390

metered dose aerosol preparations see Aerosolpreparations manufacture

microbial cultures 103microbiological monitoring

aseptic preparation 88of clean areas 88irradiated products 155

minimum pressure retention valve, definitionmoist heat sterilisation 98monkeys, WHO Requirements for Biological

Substances 107monoclonal antibodies 103

closed systems of biofermenters 105monograph name 329, 384mother liquor, definition 267Mutual Recognition Agreement (MRA) 166, 290

basis for 290batch testing/release of products imported from

country with 194benefits 290content of batch certificate for products exported

under 291countries covered by 290definition 196reference samples of finished products and 204

N

negative pressure areasbiological medicinal product manufacture 105immunological veterinary product manufacture

117non-return valve, definition 135Notified Bodies, MHRA role in overseeing 4nucleic acid amplification technology (NAT) 177

O

ointments, creams and suspensionssterile, preparation 91see also Liquids, creams and ointments

on-line control, packaging 71one-shot process (cold filling) 144operational qualification (OQ) 180


order, investigational medicinal products160

definition 158organisation chart, personnel 48outer packaging


P

packagingAPIs 240

see also Active Pharmaceutical Ingredient(API) manufacturing

batch numbers 71definition 211immediate


instructions 70batch packaging records 62batch processing records 62documentation 58, 61

investigational medicinal products 161, 163at investigator site 168

labelling immediately after 71on-line control 71operations 70

precautions when establishing systems 70outer


premises for 54printing of codes/expiry dates 71of products after unusual event 71repackaging, APIs 256secondary, reference/retention samples 205

packaging materials 70, 71API, records 231API manufacturing 240batch-coded, unused, destruction 72definition 211, 267duration of retention of samples 202investigational medicinal products 161printed materials/labels 70purchase, handling and control 70

416 INDEX

packaging materials (cont.)reference samples 204

duration of retention 202sampling 140, 141specifications 59storage areas for 55

packaging sites, reference/retention samplerequirements 202

parallel distributed products, reference/retentionsamples 205

parallel distributionmaintenance of supply chain integrity 363relabelling and repackaging 362UK guidance 361

parallel distributorslicensing and inspection 362Qualified Person employed 362

parallel importing 361reference/retention samples 205

parallel processing, biological medicinal products 105parallel trade 361parametric release 197

authorisation for 197definition 197, 199principle 197sterile products 102, 197

authorisation for 197new products 198non-compliance 199personnel required for 198pre-release requirements 198requirements for 197risk analysis of sterility assurance system 198sterilisation methods 197sterility test elimination 197terminally sterilised 197

parenteral products, inspection of containers 101penicillins

containment, in API manufacturing 225cross-contamination prevention 68hypersensitivity 113veterinary medicinal products containing 113

performance qualification (PQ) 181API manufacturing 248definition 185

personnel 48adequate numbers and qualifications 48API manufacturing see Active Pharmaceutical

Ingredient (API) manufacturingbiological medicinal product manufacture 104for cell culture and fermentation 260

clean areas 91, 92cleanliness 91clothing see Clothingcomputerised systems 146, 147cross-contamination, immunological veterinary

products 116data entry into computer 147decontamination

for biological product manufacture 104immunological veterinary products 116

Directive 2003/94/EC 309eating and drinking 51Good Distribution Practice (GDP) guidelines 342hand-washing 52handling of seed lots and cell banks 108, 123hygiene 51, 91

API manufacturing 222immunological status 104immunological veterinary product manufacture

115infectious disease 51investigational medicinal product manufacture

156, 159key personnel 48manufacturer’s licence holder obligations 317manufacturers’ obligations 272medical examination at recruitment 51medicinal gases, manufacture 127organisation chart 48prescribed conditions for manufacturer’s

undertakings for imported products 335principles of GMP and 48production 66protection against biological agents 116protective clothing 51qualifications see Qualification(s)Quality Control Department 74radiopharmaceuticals, manufacture 110restricted access 51safety 42sampling of starting and packaging materials

140for sterile product manufacture 91training see Trainingwholesale dealer’s licence obligations 352work with animal tissue or microbial culture 91see also Qualified Person(s)

pesticides, containment, in API manufacturing 225pests, entry prevention 53pharmaceutical crime 7pharmaceutical quality assurance, definition 307

INDEX 417

pharmacists, Code of Ethics, of RPSGB 288photographic documentation, Directive 2003/94/EC

310“piggy-back” authorisation 362pipework

API manufacturing 224biological product manufacture 106checking during production 67cleaning, medicinal gases 131fixed, labelling of contents 57liquids, creams and ointments manufacture 142sterile product manufacture 93

“placing on the market” 364plants, medicinal 209, 210

definition 210specifications as starting material for herbal

products 137plasma products see Blood and plasma productspoisons, technical, manufacture 54positive air pressure 93positive air pressure areas, biological medicinal

product manufacture 105post-marketing surveillance, MRHA role 3post-transfusion infections 176premises 53

ancillary areas 56API manufacturing 223biological product manufacture 105blood and plasma products 174blood donation 174containment, immunological veterinary product

manufacture 117Directive 2003/94/EC 310general requirements 53Good Distribution Practice (GDP) guidelines 344herbal medicinal product manufacture 137immunological veterinary product manufacture

116controlled access 119description in documentation 119

insect/animal entry prevention 53investigational medicinal product manufacture 159ionising radiation, use in manufacture 153lighting, temperature, humidity and ventilation 53liquids, creams and ointments manufacture 142maintenance 53manufacturer’s licence holder obligations 317manufacturers’ obligations 272medicinal gases, manufacture 127

filling areas 127separate area from non-medicinal gases 127, 128

for packaging 54positioning/siting 53prescribed conditions for manufacturer’s

undertakings for imported products 335,336

pressurised metered dose aerosol preparation 144principles 53production of premixes for medicated feedingstuffs

112Quality Control 75radiopharmaceuticals, manufacture 110sterile medicinal product manufacture 92unauthorized entry prevention 53veterinary medicinal products 112see also Production areas; Storage areas

premixes, for medicated feedingstuffs 112preparation, aseptic see Aseptic preparation; Sterile

medicinal products, manufacturePrescription Only Medicines (Human Use) Order

1997 391pressure

air see Air pressurefilling of cylinders 131moist heat sterilisation 98

pressurised metered dose aerosol preparations seeAerosol preparations, manufacture

printed materialspackaging 70, 71storage 70

proceduresdefinition 211, 267deviations from 67documentation 63Good Distribution Practice (GDP) guidelines 343instructions, documentation 58operating, for equipment 65for recording actions/conclusions (various) 64release and rejection 64sampling 64testing of materials/products 64written

complaints on products 83recall of products 84

see also individual procedures/operationsprocess aids, definition 267process control see In-process controlprocess equipment see Equipmentprocess simulation test, validation of aseptic

processing 95process validation 181

see also Validation

418 INDEX

processing/processing operationsafter harvesting, of biological products 105documentation, investigational medicinal products

161instructions

documentation 60, 61herbal products 138investigational medicinal products 160

intermediate and bulk products 70ionising radiation, use in manufacture 154

electron beam irradiators 155gamma irradiators 154

sterile medicinal products, manufacturecontamination minimisation 95minimisation of time intervals 96validation 95

sterile product manufacture 95Product Licence 279Product Licence for Parallel Import (PLPI) 362, 363product quality review see Quality reviewproduct recall see Recall of productsproduct specification file

definition 158investigational medicinal products 160, 166

production 66API

responsibility for and quality management 221see also Active Pharmaceutical Ingredient (API)

manufacturingbiological medicinal products see Biological

medicinal products manufactureblood and plasma products 176cross-contamination prevention 67definition 211, 267deviation from procedures/instructions 67different products in same room 66discrepancies between bulk product and packaged

product 72finished products see Finished productsgeneral issues 66handling of materials/products 66herbal medicinal product manufacture 137immunological veterinary products 122instructions see Processing/processing operations,

instructionsinvestigational medicinal products see

Investigational medicinal products(manufacture of)

liquids, creams and ointments 142medicinal gases 129

bulk production 129

filling and labelling 132methods, re-validation 68new formulae/methods, validation 68packaging see Packaging; Packaging materialspersonnel 66premixes for medicated feedingstuffs 112pressurised metered dose aerosol preparations 144principles 66processing operations see Processing/processing

operationsradiopharmaceuticals 111starting materials see Starting materialsvalidation 68

production areas 53design 54

biological medicinal product manufacture106

drains 54fittings (pipes, lights and services) 54herbal medicinal product manufacture 137immunological veterinary product manufacture

118disinfection 125operating principles 123

in-process controls 55lighting 55liquids, creams and ointment manufacture 142non-medicinal vs medicinal products 67restricted access 67stocks of substances for biological products 106ventilation 54walls, floors and ceilings 54working and storage space 54see also Premises

professional conduct, Qualified Persons 286professional misconduct, Qualified Person(s) 282,

287prospective validation 181, 182


protective clothing see Clothingpurge, gas cylinder, definition 135purification

APIs produced by cell culture/fermentation 261medicinal gases 129

Q

qualification(s) 179, 180API manufacturing 222, 248completion, written authorisation 180

INDEX 419

definition 211, 267design (DQ) 180


documentation 179of established (in-use) facilities/systems/equipment

181installation (IQ) 180


operational (OQ) 180API manufacturing 248definition 185

performance (PQ) 181API manufacturing 248definition 185

of personnelfor API manufacturing 222Qualified Persons 303

principle 179Qualified Person(s) see Qualified Person(s),

qualificationsvalidation and 179, 248

Qualified Person(s) 43, 44, 48, 196, 275absence, areas of work operating in 282assessment by licensing authority 275, 276batch release 187

see also Batch release, and certification for (byQP)

certification by 187, 278EU directives 187, 277principle 187rationale 188requirements before certification 194responsibilities for see belowscope of guidance/annex 187see also Batch release

certification of by professional bodies 286certification of products for sale 46, 90Code of Practice (UK) (details) see Code of Practice

for Qualified Personscommitment to meet professional colleagues 281complaints to/awareness of 83compliance of intermediate stage of manufacture

195compliance with Marketing Authorisation 283concept, introduction 276consultation with other experts 281

maintenance of register 281continuing professional development see

Continuing professional development (CPD)

contract manufacture and analysis 284contracted 283

duties 284definition 196, 307disciplinary procedures 287duties 48, 283, 286

Directive 2001/83/EC 306see also Qualified Person(s), routine duties

eligibility to certify batches 278, 303investigational medicinal products, duties 168knowledge/experience 195, 304, 305, 320legal responsibilities 277licensing authority’s requirements 321medicinal gases, manufacture 127The Medicines for Human Use (Manufacturing,

Wholesale Dealing and MiscellaneousAmendments) Regulations 2005, requirements320

memberships 321number and location 283at parallel distributors 362performance of duties and regulatory compliance

282present at manufacturing site 283product quality review 47product specification file for investigational

medicinal products 160professional conduct 286professional duties on knowledge/experience 278professional misconduct 282, 287qualifications 303, 305, 320

notification by licence holder 321university courses, subjects included 304

Quality Control of radiopharmaceuticals 111quality management aspects 279recall of products

awareness of 84identification of QP 188

reference sample retention 281regulatory basis for 277requirements for 276, 303responsibilities for certification 188, 278, 282

batch testing/release of products imported fromcountry with mutual recognition agreement194

general issues/requirements 188Mutual Recognition Agreements and 290products imported from third country 192, 281,

290, 306products manufactured in EC/EEA 190reference/retention sample storage 204

420 INDEX

Qualified Person(s) (cont.)see also Batch release, and certification for

(by QP)responsibilities for securing products 305results of on-going stability testing 79role in contract manufacture 81routine duties 194, 280

size of company influence 281training for new responsibilities 285working relationship with colleagues 282working relationship with Regulatory Inspectors

286Quality Assurance (QA) 43

API manufacturing 219blood and plasma products 173definition 268definition and scope 43, 307Directive 2003/94/EC 309GMP see Good Manufacturing Practice (GMP)investigational medicinal products 158methods acceptable 42prescribed conditions for manufacturer’s

undertakings for imported products 335sampling of starting material 140see also Quality management

Quality Control 45, 74API manufacturing 219areas 55biological medicinal product manufacture 109

in-process controls 109blood and plasma products 176definition 45, 268Directive 2003/94/EC 311documentation 75duties of head of department 74general issues 74Good Laboratory Practice 75herbal medicinal product manufacture 139immunological veterinary product manufacture

126independence 74investigational medicinal products 165manufacturers’ obligations 273medicinal gas manufacture 132on-going stability programme 77premises 75prescribed conditions for manufacturer’s

undertakings for imported products 335pressurised metered dose aerosol preparations 144principle and definition 74radiopharmaceuticals 110, 111

requirements 45batch records 75

returned products 73sampling 76sterile product manufacture 102testing 76training of personnel 51

Quality Control Departmentduties 74personnel 74requirement for 74

Quality Control Laboratories 55biological/radioactive samples 56design and space 56for sensitive equipment 56siting of 55

quality defects in products, reporting to MHRA 6quality management 41, 43, 342

Active Pharmaceutical Ingredients 219agents, brokers, traders, distributors, repackers

and relabellers 256for use in clinical trials 262see also Active Pharmaceutical Ingredient (API)

manufacturingblood and plasma products 173“Good Manufacturing Practices” 279investigational medicinal product manufacture 158principle 43

quality review, API manufacturing 222quality review, of products 46

assessment and evaluation 47description and requirements 46rolling reviews 46

quality system, wholesalers 342quality unit(s), definition 268quarantine

animals, for biological product manufacture 106definition 211, 268finished products 72of incoming materials and products 66materials for API manufacturing 235

quarantine status, storage areas and 55

R

radiationionising see Ionising radiation, use in manufacturesterilisation by 99

radiation dose 99monitoring during manufacture 154sterilisation 99

INDEX 421

radiation indicators 154radiation-sensitive colour disks, monitoring radiation

sterilisation 99radiation-sensitive materials 99radiation sterilisation 99radiation treatment see Ionising radiation, use in

manufactureradioactive samples, Quality Control Laboratories

56radiopharmaceuticals, definition 211radiopharmaceuticals, manufacture 110

distribution and recalls 111personnel 110premises and equipment 110principle 110production 111Quality Control 110, 111sterile products 110

randomisation, definition 158randomisation code 163

definition 158Rapporteur 4raw materials

API manufacturing, records of 231control, API production 263definition 268

recall of products 83, 84APIs 254

handling by agents/brokers/traders 257Directive 2003/94/EC 313distribution record requirement 84emergency plan for 346follow-up after 367GMP requirement 45Good Distribution Practice (GDP) guidelines 346identification of Qualified Person involved 188informing authorities 84initiation 84investigational medicinal products 169management of recall 367prescribed conditions for manufacturer’s

undertakings for imported products 337principle 83radiopharmaceuticals 111“recall” issued 366recording of progress and effectiveness 84responsible persons 84storage of products after 84UK guidance and obligations 366written procedures 84

receipts, for deliveries 63

recombinant DNA technology 103APIs produced by 258

recommissioning, of plant for ionising radiation use153

reconciliation, definition 212reconstituted products, stability 78records 63

API manufacturing see Active PharmaceuticalIngredient (API) manufacturing

aseptic processing 95batch see Batch recordscell banks 260cleaning 230complaints on products 83

APIs 254consultants, Active Pharmaceutical Ingredients

(API) 223contract manufacture 82distribution of batches of products 64for GMP 45Good Distribution Practice (GDP) guidelines 343imported products

manufacturer’s licence and 328prescribed conditions for manufacturer’s

undertakings for 336log books on equipment 65of product batches, documentation 58on product recall 84Quality Control requirement 45, 90of sampling 64self inspection 85standard provisions for manufacturer’s licence

relating to sera 334standard provisions for manufacturer’s licence

relating to vaccines 330starting materials 64sterilisation 97

with ethylene oxide 100testing of materials/products 64wholesale dealer’s licence 379wholesale dealer’s obligations 351, 352wholesale distribution authorisation 374see also Documentation

recovered materials 72recovery

of batches 72definition 212

recruitment, medical examination at 51reference samples 76, 201

definition and rationale for 201duration of storage 202

422 INDEX

reference samples (cont.)finished products 204

products manufactured outside EEA 204packaging materials 202parallel imported/distributed products 205principle 201requirements for 202responsibilities of QP 281sizes 202starting materials 204storage conditions 203storage site and availability 204traceability 202written agreements 203

reference standardslaboratory, API manufacturing 244primary 244

definition 268“in-house” 244

secondary 244definition 268

refuse and waste, API manufacturing 226rejected materials 72, 236, 252

APIs see Active Pharmaceutical Ingredient (API)manufacturing

blood/plasma products, disposal 178reprocessing see Reprocessingstorage areas 55

relabellers, APIs 256relabelling

APIs 256investigational medicinal products 168UK guidance 362

release of product see Batch release, and certificationfor (by QP)

repackagingAPIs 256UK guidance 362

repackers, APIs 256reprocessing

definition 212, 268of materials, API manufacturing 253of rejected materials 72testing of finished product after 72

reserve samplesAPIs 246see also Retention samples

Responsible Person (RP)appointment/duties 355contract on duties/responsibilities 355deputy 356

experience 356pharmaceutical knowledge 355requirements for carrying out responsibilities 356UK legislation requirement 381

rest rooms 56retail sales, manufacturers’ obligations 273retention samples 201

APIs 246biological medicinal products 109blood and plasma products 177definition and rationale for 201different EEA manufacturing sites 205duration of storage 202, 312immunological veterinary products 126investigational medicinal products 166location/storage site 204, 205medicinal gases 133packaging in two processes 203parallel imported/distributed products 205prescribed conditions for manufacturer’s

undertakings for imported products 337principle 201products manufactured outside EEA 205requirements for 202sizes 202storage conditions 203traceability 202veterinary medicinal products 113written agreements 203

retest dateAPIs 246definition 269

retesting, APIs 246retrospective validation 183


return, definition 212returned materials/products 72

APIs 254handling by agents/brokers/traders 258

blood and plasma products 174destruction 73Good Distribution Practice (GDP) guidelines

345investigational medicinal products 168, 169non-defective products, Good Distribution Practice

(GDP) guidelines 345products classified as not for sale 347quality control and assessment 73

revalidation 184definition 186

INDEX 423

reworking of batchesAPIs 253definition 269

risk analysisdefinition 186sterility assurance system, for parametric release

198rodents

prevention in manufacture of herbal products137

prevention in manufacture of premixes 112Royal Pharmaceutical Society of Great Britain

Code of Ethics for pharmacists 288CPD statement 288

Royal Society of Chemistry, CPD statement 289

S

safe use of medicines, MHRA role in promoting 4safety cabinets 105safety of personnel 42sales, manufacturers’ obligations 273samples

APIs 246for batch release and certification see Batch release,

and certification for (by QP)blood and plasma products 177prescribed conditions for manufacturer’s

undertakings for imported products 337quality control

Directive 2003/94/EC 312investigational medicinal products 166see also Quality Control

radioactive, Quality Control Laboratories 56reference see Reference samplesreserve, APIs 246retention see Retention samplesshared responsibility for 50sizes and number, API manufacturing materials

236stability testing, of APIs 245sterile products 101, 102storage 56, 203

samplingarea, for starting materials 55aseptic operations 88biological products 108cleaning validation in API manufacturing

250containers for 76herbal medicinal products 138

in-process, API manufacturing 238incoming materials for API manufacturing

235packaging materials 140personnel 140principle 140procedures and records 64, 76Quality Control 76reference samples 76starting materials 140sterility testing of sterile products 102see also Reference samples; Retention samples;

Samplessanitary status, animals 121sanitation

API manufacturing 226of clean areas 94personnel, API manufacturing 222, 224

seals, broken 344security

computerised systems 229of personnel 42

seed lot system, definition 212seed lots 107

biological product manufacture 107contamination 108

prevention 108testing and characterisation 123

definition 212establishment 123generation number between finished product and

107, 122immunological veterinary product manufacture

122master, definition 212personnel handling 108, 123stability and storage 108storage 123working, definition 212

self inspection 85API manufacturing 221conduction and independent audits 85Directive 2003/94/EC 313Good Distribution Practice (GDP) guidelines 347principle 85procedure, in Quality Assurance system 44programme components 85recording and reports 85

sera, manufacturer’s licences, standard provisions for322, 333

sewage, API manufacturing 226

424 INDEX

shelf life, testing and monitoring programme 77shipping

investigational medicinal products 168definition 158

see also Deliveries; Distributionsignatures

electronic 230signed, definition 269

simulated product, definition 186single-blinding, definition 157sinks and drains, sterile product manufacture 93smallpox vaccines, standard provisions in

manufacturer’s licence 330smoking, restrictions 223software 147

API manufacturing 229solvents

definition 269recovery, API manufacturing 254

“specials”Guidance Notes 7importation and manufacture 294wholesale dealer’s licence obligations 353

specifications 59API manufacturing, documentation and records

229biological products 107bulk products 60definition 269documentation 58, 59finished products 60herbal medicinal products, manufacture 137intermediate products 60ionising radiation, use in manufacture 150medicinal gases 130, 132metered dose aerosols 144packaging materials 59starting materials 59, 107testing (analysis) 76see also Documentation

spillages, immunological veterinary productmanufacture 123, 124

sponsors, investigational medicinal products 167,168, 169

definition 158spore-forming bacteria 105, 118stability

APIs 257bulk products 77monitoring, of APIs 245on-going testing programme 77

animals required for 78batch number and frequency 78equipment for, maintenance 78out of specification/atypical trends 79protocol, inclusions 78protocol, long-term stability study vs 78purpose 77result disclosure 79written protocol 78

premixes for medicated feedingstuffs 112reconstituted products 78seed lots and cell banks 108

starting materials 68active substances see Active Pharmaceutical

Ingredient (API); Active substance startingmaterials

batches 69labelling for use 69

biological, specifications 107biological product manufacture 107bulk, liquid, cream and ointment production 142containers for 69contamination 67content identification 69definition 212delivery 69dispensing 69GMP for 293health status of animals 107herbal product manufacture 137identification/identity testing 140immunological veterinary product manufacture

122media 122operating principles 123processing before analytical results 122seed lot and cell bank system 122sterilisation 122suitability and specifications 122transfer of materials 124

labelling 69manufacturers’ obligations 272microbial contamination 96offence relating to sale/supply (Medicines for

Human Use Regulations) 322parametric release and 199purchase 68

approved suppliers 69purchased intermediate/bulk products 66quality assessment 141Quality Control checking 69

INDEX 425

records 64reference samples see Reference samplessampling 140

method 140validation 140

specifications 59herbal product manufacture 137

sterile, handling 90sterilisation 122

for biological product manufacturestorage, labelling of 69weighing 54

statutory obligations relating to medicines, MHRArole in monitoring compliance 4

steamadverse effect on product 112penetration and quality 98sterilisation 98

sterile medicinal products, manufacture 86Active Pharmaceutical Ingredients, water quality

for 225active substance starting materials 216aseptic preparation 90blow/fill/seal technology 90change control 198clean areas, classification 86closure of containers 101equipment 94finishing 101general issues 86GMP guide (EU) coverage 86high-risk of contamination 90investigational medicinal product 162isolator technology 89monitoring of aseptic areas/operations 88operation categories 86parametric release 102, 197

see also Parametric releasepersonnel 91premises 92principle 86processing 95Quality Control 102radiopharmaceuticals 110sanitation 94site/location and areas 86

“at-rest” and “in operation” states 87Grade A 87Grade A, clothing and hair 92Grade B 87Grade B, clothing and hair 92

Grade C 87Grade C, clothing and hair 92Grade D 87Grade D, clothing 92operations at site grades 88

sterilisation see Sterilisationsterility testing 102storage 100terminally sterilised products 90validation 198veterinary products 114see also Clean areas; Equipment;

Processing/processing operationssterilisation

active substance starting materials 217bioburden see Bioburdenbiological indicators for monitoring 97culture media 109dry heat 99effective, requirements 97, 98equipment 94, 96

immunological veterinary products 120ethylene oxide 100filtration of products 100heat 97, 98immunological veterinary product manufacture

118, 124“in place” systems 106media, immunological veterinary product

manufacture 122methods, parametric release and 197moist heat 98precautions 95quality control 102radiation 99records 97

checking for parametric release 198starting materials, for biological product

manufacture 107steam 98suitability for products 97validation of procedures 97

“sterilise in place” systems 106sterilised products

differentiation from non-sterile products 97terminal phase of production 90

sterilisers, moist heat sterilisation 98sterility, definition 213sterility assurance system 199

definition 199risk analysis, for parametric release 198

426 INDEX

sterility test/testingsampling 102for sterile products 102, 197

elimination, parametric release 197storage

APIs 242materials for API manufacturing 236

of biological agents, equipment 120blood and plasma products 176cell bank system 108cold 357conditions, reference/retention samples 203duration, for reference/retention samples

202equipment 120finished products 72herbal medicinal products 137immunological veterinary products before

completion 125labelling of goods 69laboratory reagents 77liquids, creams and ointments 142, 143manufacturers’ obligations 272of materials 66medicinal gases 128, 133packaging materials 55printed materials 70of products, Good Distribution Practice (GDP)

guidelines 344“first in first out” 344requirements of facilities 344

radioactive products 110recalled products 84rejected materials 55returned products 73samples 56, 202seed lots and cell banks 108, 123starting materials 69sterile products 100temperatures see Temperature(s)

storage areas 55herbal medicinal product manufacture

137highly active materials/products 55packaging materials 55in production area 54quarantine status and 55recalled/rejected or returned products 55receiving/dispatch bays 55sampling of starting materials 55temperature 55

swab sampling, cleaning validation in APImanufacturing 250

system, definition 186, 213

T

tank(s)medicinal gases 128

definition 136storage, liquid, cream and ointment production

142tankers

bulk deliveries in API manufacturing 235medicinal gases, definition 136

Technical Agreements, for quality review 47temperature(s)

alarms 358clean areas 96controlled room, storage 358extreme, in delivery vehicles 359medicinal gas manufacture 130moist heat sterilisation 98premises 53, 54refrigerators, monitoring 357storage

blood and plasma products 176control and monitoring 357of products, Good Distribution Practice (GDP)

guidelines 344storage areas 55system checks and calibration 359transportation, control and monitoring 357warehouses 358

temperature probes, heat sterilisation monitoring 98terminally sterilised products 90

parametric release 197“test until clean” 184testing (analysis)

animals used for 77blood and plasma products 176contracts for 81data required 76date of receipt of substances 77documentation, investigational medicinal products

161finished product after reprocessing 72imported products, manufacturer’s licence 326in-process controls 77incoming materials for API manufacturing 235intermediates and APIs 244of laboratory reagents and equipment 77

INDEX 427

manufacturers’ obligations 274method validation 76procedures and records 64products manufacture and imported from in third

country 192EC/EEA sites 193

Quality Control 76recording of results 76retest dating, of APIs 246specifications 76stability see Stabilitysterility see Sterility test/testingvalidation 76see also Contract manufacture and analysis

toiletsAPI manufacturing facilities 224positioning 56

toxic non-pharmaceutical materials, containment, inAPI manufacturing 225

toxins, manufacturer’s licences, standard provisionsfor 322, 333

traceabilityof blood and plasma products see Blood and

plasma productsof distributed APIs/intermediates 256of investigational medicinal products 159, 160,

170of reference and retention samples 202

trademarks 327, 353traders, APIs 256training, of personnel 50

API manufacturing 222biological product manufacture 104for computerised systems 146Directive 2003/94/EC 309hygiene 51immunological veterinary product manufacture

115Qualified Persons 285

university courses 303Quality Control 51radiopharmaceutical manufacture 110requirements and need 50sampling of starting and packaging materials 140sterile product manufacture 91for work with hazard areas 51see also Continuing professional development

(CPD)transfer operations

of APIs 242clean areas 96, 124

contained area 124investigational medicinal products 168liquid, cream and ointment production 142medicinal gas manufacture 130

transportationof APIs 242cold-chain goods 358temperature

control and monitoring 357extreme 359system checks and calibration 359UK guidance 358

UK guidance 358see also Deliveries; Distribution

transposition, Directive 2003/94/EC 314tuberculin products 104, 105tuberculosis, BCG vaccine manufacture, standard

provisions 332two-shot system (pressure filling) 144, 145

U

UK guidancemanufacture

manufacturers’ obligations 272Qualified Persons see Qualified Person(s)

wholesale distribution practice 349see also Wholesale distribution; Wholesalers

UK legislation 389primary 389secondary 390see also The Medicines for Human Use

(Manufacturing, Wholesale Dealing andMiscellaneous Amendments) Regulations2005

unblinding 161definition 157, 307emergency 164

Directive 2003/94/EC 313unlicensed medical products

Guidance Notes 7importation and manufacture 294

CJD transmission risk minimisation 296for individual patients 295“specials” 294

manufacture and importation 294The Unlicensed Medicinal Products for Human Use

(Transmissible Spongiform Encephalopathies)(Safety) Regulations 2003 391

use-by date, investigational medicinal products165

428 INDEX

V

vaccination, personnel, for biological productmanufacture 104

vaccinesanimal use, standard provisions for manufacturer’s

licence relating to vaccines 330BCG, standard provisions in manufacturer’s licence

331cross-contamination prevention 68manufacturer’s licences, standard provisions for

322, 329smallpox, standard provisions in manufacturer’s

licence 330vacuum sealing, containers 101validation 179

analytical methods 76API manufacturing see Active Pharmaceutical

Ingredient (API) manufacturingaseptic processing 95

investigational medicinal product 162blood and plasma products

testing 176virus removal/inactivation 177

campaign working 54change control 184cleaning see Cleaning validationcomputerised systems 146concurrent 181, 182


definition 213, 269documentation 179equipment 181

for sterile product manufacture 94facilities 181immunological veterinary production 125investigational medicinal product production

162ionising radiation, use in manufacture 150,

155isolator technology 89new procedures in clean areas 96, 97planning for 179principle 179process 181, 185

API manufacturing 248, 263batches for retrospective validation 183batches/process run number 182components included 182data for retrospective validation 183

definition 185general issues 181sale of validation batches 182timing of and completion 181

production 68prospective 181, 182


qualification and 179, 248radiation sterilisation 99retrospective 181, 183


revalidation 184definition 186

sampling of starting materials 140sterile products 198sterilisation by ethylene oxide 100sterilisation procedures 97testing (analysis) 76virus removal from blood/plasma products

177validation master plan (VMP) 179valves

gas containers, definition 136metering, pressurised metered dose aerosol

preparations 144minimum pressure retention, definition 135non-return, definition 135

variant Creutzfeldt-Jakob disease (vCJD) 175vegetable drug preparations 139, 209

processing 138ventilation

API manufacturing facilities 224premises 53production areas 54see also Air supply

veterinary medical products, manufacture 112containers for 113ectoparasiticides 113GMP requirements 41immunological products see Immunological

veterinary productspremixes for medicated feedingstuffs 112products containing penicillins 113retention of samples 113sterile products 114

Veterinary Medicines Directorate 6vials, capping, immunological veterinary product

manufacture 125viral markers 175

INDEX 429

viruses, inactivation/removal 109APIs produced by cell culture or fermentation

261from plasma-derived medicinal products 174,

177testing 176

see also Infectious diseasevisitors 51, 104

W

warehouses, temperatures 358warehousing procedures, APIs 242washing

equipment 56facilities, API manufacturing 224personnel 91

waste disposal see Disposal of productswaste handling, immunological veterinary product

manufacture 118water

API manufacturing 225chemical sanitisation and flushing after 142distilled, deionized 57drinking, WHO guidelines 225for injections 94liquids, creams and ointments production

142medicinal gas manufacture 130, 132

water sources, aseptic processing 95water treatment plants, sterile product manufacture

94weighing

calibration 57cross-contamination prevention 54starting materials 54

weighing rooms 54wholesale dealer’s licence

appointment/duties of responsible person 355documentation 379Guidance Notes 7imported products 380information supplied with products 352obligations 349, 378

“specials” 353personnel required 352requirement to deal with specified persons only

380standard provisions (UK) 382supply sources 351UK legislation 378

wholesale distributionEU guidance 341

see also Good Distribution Practice (GDP)EU legislation 371

authorization 372documentation 375guidelines on good practice 375homeopathic products 375minimum requirements 373public service obligations 374restricted products 375time frame for authorisation application

373UK guidance 349

checking bona fides of supplier/products360

continued supply 363counterfeits 359diverted medicines 360maintenance of supply chain integrity 363obligations of dealer 349parallel distribution 361product recall/withdrawal 366relabelling/repackaging 362responsible person see Responsible Person

(RP)storage/transportation temperatures 357see also Wholesale dealer’s licence

UK legislation 3772005 Act and Regulations 377dealing with specified persons only 380requirement for responsible persons 381standard provisions (Schedule 4) 382wholesale dealer’s licence obligations 378see also Wholesale dealer’s licence

wholesalersDirective 92/25/EEC 342GDP Inspectors’ role 5manufacturer’s licence holder obligations

319obligations, UK guidance 349orders from, guidelines 343provision of information to member states

347quality system 342see also Distributors

withdrawal of productsblood and plasma product batch 176UK guidance 366UK guidance and obligations 366see also Recall of products

430 INDEX

workshops, maintenance 56World Health Organization, certificates

supporting quality of pharmaceuticalproducts 6

“worst case” approachcleaning validation 184definition 186

wristwatches, wearing 92

Y

yielddeviations from expected 70expected, definition 270manufacturing processes 61Quality Control records 75theoretical, definition 270